ACKR4a Induces Autophagy Los Thaiv NF-kB Kev Tshaj Tawm Thiab Apoptosis Los Pab Kom Vibrio Harveyi Kab Mob
Nov 29, 2023
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Autophagy thiab apoptosis yog ob qho kev pom zoo ntawm kev tiv thaiv kab mob ntxeem tau. Txawm li cas los xij, cov kab mob kuj tau hloov kho lub peev xwm los tiv thaiv kev tiv thaiv. Hauv txoj kev tshawb no, peb txheeb xyuas ACKR4a, tus tswvcuab ntawm tsev neeg atypical chemokine receptor, ua tus tiv thaiv ntawm NF-kB txoj hauv kev, uas koom tes nrog Beclin -1 txhawm rau ua rau autophagy inhibit NF-kB signaling thiab thaiv apoptosis, ua kom yooj yim. Vibrio harveyi kab mob. Mechanistically, V. harveyi-induced Ap-1 activates ACKR4a transcription thiab qhia. ACKR4a tsim ib txoj hauv kev nrog Beclin-1 thiab MyD88, raws li txoj cai, inducing autophagy thiab thauj MyD88 mus rau hauv lysosome rau degradation los suppress inflammatory cytokine ntau lawm. Lub caij no, ACKR4a-induced autophagy blocks apoptosis los ntawm inhibiting caspase8. Qhov kev tshawb fawb no ua pov thawj thawj zaug uas V. harveyi siv ob qho tib si autophagy thiab apoptosis kom tsis txhob muaj kev tiv thaiv kab mob hauv lub cev, qhia tias V. harveyi tau hloov kho lub peev xwm tiv thaiv ntses.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Taw qhia
Lub cev tiv thaiv kab mob feem ntau muab faib ua innate thiab tau txais kev tiv thaiv kab mob, nrog rau cov kab mob feem ntau vam khom hauv lub cev tiv thaiv kab mob rau kev ciaj sia.1 Lub cev tiv thaiv kab mob yog ib qho kev tiv thaiv uas tsim los ntawm cov kab mob. Nws paub txog cov kab mob sib txuas nrog cov qauv molecular (PAMP) los ntawm cov qauv lees paub receptors (PRRs), ua rau cov lus teb sai rau cov kab mob pathogenic, thiab tiv thaiv tus tswv tsev los ntawm kev kis kab mob.2,3 Raws li ib qho tseem ceeb PRR, hu xov tooj zoo li receptors (TLRs) tuaj yeem pib ntau cov lus teb los ntawm phagocytosis mus rau cytokine ntau lawm, yog li ntxiv dag zog rau cov kab mob hauv lub cev thiab lub cev tiv thaiv kab mob.4 Feem ntau, TLRs teeb liab feem ntau los ntawm MyD88- txoj hauv kev, uas xa cov teeb liab los ntawm kev cuam tshuam los ntawm kev ua kom muaj zog nuclear. factor-kappa B (NF-kB).5 NF-kB yog ib qho tseem ceeb hauv kev pib ntawm kev tiv thaiv kab mob hauv lub cev thiab yog qhov tseem ceeb rau kev sib koom ua ke ntawm cov kab mob inflammatory, innate tiv thaiv, cell sib txawv, kev loj hlob, thiab ciaj sia taus, thiab yog suav hais tias yog tus thawj coj tseem ceeb ntawm cov lus teb inflammatory.6 Thaum cov kab mob kis mus rau tus tswv tsev, cov nyhuv downstream ntawm lub cev tiv thaiv kab mob xws li cytokines thiab chemokines yog synthesized, thiab thaum kawg ua rau cov kab mob inflammatory los thaiv kev loj hlob ntawm cov kab mob. Txawm li cas los xij, nyob rau hauv kev sib koom tes nrog lawv cov tswv, cov kab mob kuj tau tsim ntau yam kev cai tswj hwm kom khiav tawm thiab rhuav tshem lawv tus tswv tsev tiv thaiv.
Autophagy thiab apoptosis tau xav tias yog ob txoj hauv kev tseem ceeb tiv thaiv kab mob ntxeem tau.7 Autophagy yog cov txheej txheem khaws cia uas thauj cov protein ntau txawv txav mus rau lysosomes rau degradation thiab plays lub luag haujlwm tseem ceeb hauv kev tiv thaiv innate ntawm eukaryotes tiv thaiv kab mob ntxeem tau.8,9 Txawm li cas los xij, qee qhov Cov kab mob evade tiv thaiv kab mob los ntawm kev siv autophagy hauv cov tsiaj. Nquag, cov hlwb tsom kom tshem tawm cov kab mob hauv cov kab mob extracellular thiab colonizing cov kab mob hauv cytoplasm los ntawm autophagy, 10 tab sis qee cov kab mob tuaj yeem 'hijack' autophagy kom ua tiav nws tus kheej loj hlob thiab rov tsim dua.11–13 Piv txwv li, Unc-51-zoo li kinase 1 (ULK1), Beclin1, microtubule-associated protein light chain 3 (LC3), thiab autophagy-related proteins (ATGs) koom tes tsim autophagosomes, uas encapsulate invading microorganisms thiab thauj lawv mus rau lysosomes rau degradation.14-16 Txawm li cas los, Mycobacterium tuberculosis down -regulates Beclin{18}} los tiv thaiv autophagosome tsim, thaum kawg inhibiting autophagy thiab txhawb kev kis kab mob.17 Nyob rau hauv sib piv nrog rau inhibition ntawm autophagosome tsim, ib co kab mob siv autophagosomes ua kom tiav nws tus kheej replicating qhov chaw los txhawb proliferation.11,18 Ntxiv rau autophagy, apoptosis kuj yog ib txoj hauv kev los tiv thaiv tus tswv tsev tiv thaiv cov kab mob invading.7 Apoptosis yog cov qauv kev tuag ntawm tes siv los tshem tawm cov hlwb puas los tswj kev ruaj ntseg ntawm lub cev ib puag ncig.19 Thaum tau txais cov teeb liab ntawm cov kab mob ntxeem tau, tus tswv tsev induces apoptosis ntawm tus kab mob. hlwb los tiv thaiv kab mob.20 Yog li ntawd, kev vam meej kab mob colonization nyob ntawm nws lub peev xwm los tiv thaiv apoptosis thiab tiv thaiv kab mob replication. Piv txwv li, Edwardsiella tarda ua kom nws txoj sia nyob los ntawm inhibiting apoptosis tom qab kab mob ntawm zebrafish ZF4 hlwb, 21Shigella ua tiav txoj kev vam meej los ntawm inhibiting apoptosis, 22 thiab S protein uas tsim los ntawm pab pawg A streptococcus (GAS) khi rau erythrocyte daim nyias nyias kom evade nrhiav tus tswv tsev tiv thaiv kab mob. system.23 Txawm hais tias muaj ntau cov kab mob tau raug pov thawj tias muaj peev xwm tiv thaiv kev tiv thaiv kab mob, muaj ob peb daim ntawv qhia txog cov kab mob marine. Vibrio harveyi belongs rau tsev neeg Vibrionaceae, uas tau lees paub tias yog tus neeg sawv cev ntawm cov ntses marine; nws ua rau plab hnyuv, nqaij necrosis, thiab daim tawv nqaij ulcers, thiab yog ib qho ntawm cov tseem ceeb ua rau cov ntses marine mortality.24
cistanche cog-nce kev tiv thaiv kab mob
Tsuas yog rau autophagy thiab apoptosis, qee cov kab mob (xws li Staphylococcus aureus) tuaj yeem siv lawv tus tswv tsev cov tshuaj chemokine receptors los tiv thaiv kev tiv thaiv kab mob.25 Chemokine receptors yog G protein-coupled receptors (GPCRs) pom feem ntau ntawm cov leukocytes. Lawv muaj xya cov qauv transmembrane, uas koom nrog ligand khi thiab kev taw qhia, thiab ua lub luag haujlwm tseem ceeb hauv kev pib thiab kev saib xyuas lub cev tiv thaiv kab mob thiab inflammatory teb.26 Raws li kev tshawb fawb chemokine tau nce, atypical chemokine receptors (ACKRs) tau tshawb pom.27 Txawm hais tias ACKRs yog structurally zoo ib yam li lwm yam chemokine receptors thiab muaj peev xwm internalize ligands, lawv tsis muaj peev xwm qhib lub teeb liab transduction txoj kev vim tsis muaj lub DRYLAIV domain, uas tseem hu ua 'silent receptor'.28 Lub luag hauj lwm ntawm ACKRs tej zaum yuav tshwm sim nyob rau hauv cov nram qab no txoj kev. : 1. Lawv tuaj yeem sib tw nrog cov receptors raug khi rau chemokine, thiab yog li, tswj cov teeb liab hloov ntawm cov cell chemotaxis; 2. Los ntawm internalizing chemokine rau hauv cov hlwb, qhov concentration ntawm chemokine nyob rau hauv ib puag ncig raug txo kom muaj feem xyuam rau cov cell recruitment thiab ua raws li ib tug chemokine scavenger. 3. Lawv pab chemokines kom ua tiav kev thauj mus los ntawm tes los ntawm stromal cell barrier.29 ACKRs tsev neeg feem ntau suav nrog DARC, 30 D6 31,32, CXCR7,33 thiab CCRL1,34 CCRL1 kuj hu ua atypical chemokine receptor. 4 (ACR4). Tam sim no, qee qhov kev tshawb fawb tau pom tias ACKR4 zoo li paub txog kev hloov pauv ntawm G protein txoj hauv kev ywj pheej, 35-37 thiab nws muaj lub luag haujlwm tsis txaus ntseeg hauv kev tswj kev mob thiab tiv thaiv kab mob.38 Nws lub luag haujlwm hauv kev tiv thaiv kab mob yog paub zoo, tab sis nws kev ua haujlwm hauv lub cev tiv thaiv kab mob tsis tshua tau kawm.
Nyob rau hauv lub cev tiv thaiv kab mob, lub teeb liab hloov ntawm TLR txoj kev yog heev txuag los ntawm invertebrates mus rau tsiaj. Raws li cov ntsiab lus tseem ceeb ntawm TLR signaling, MyD88 tau kawm dav hauv cov vertebrates. Tsis tas li ntawd, vim hais tias ntawm cov qauv kev txuag heev ntawm MyD88, nws homologs hauv cov ntses yuav muaj cov haujlwm zoo sib xws rau cov tsiaj hauv cov tsiaj.39,40 Hauv zebrafish, MyD88 koom nrog kev tshem tawm cov kab mob.41 Cov kev tshawb fawb yav dhau los kuj tau lees paub tias V. harveyi evades kev tiv thaiv los ntawm kev rhuav tshem cov teeb liab hloov ntawm MyD88.42 Txawm li cas los xij, cov txheej txheem ntawm yuav ua li cas V. harveyi evades kev tiv thaiv tsis zoo nyob rau hauv cov ntses teleost. Hauv txoj kev tshawb no, ACKR4a tau ceev ceev-tswj hauv V. harveyi-stimulated Miichthys muy. Kev tswj hwm ACKR4a ob leeg tau txwv tsis pub muaj kev tiv thaiv hauv lub cev los ntawm kev ua kom tsis muaj zog los thaiv MyD88-txoj kev kho NF-kB thiab ua rau autophagy los thaiv apoptosis, txhawm rau txhim kho V. harveyi kab mob. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, daim ntawv tshaj tawm no yog thawj zaug qhia tias V. harveyi tau pom tias siv ob qho tib si autophagy thiab apoptosis kom tsis txhob muaj kev tiv thaiv hauv lub cev.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
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V. harveyi kab mob induces ACKR4a qhia los txhawb nws tus kheej proliferation
Txhawm rau txheeb xyuas cov noob uas muaj feem cuam tshuam nrog kev tswj hwm ntawm V. harveyi kab mob, peb tau kho miiuy croaker nrog V. harveyi rau 48 h, tom qab ntawd siv RNA-seq tsom xam los tshuaj xyuas cov kab mob sib txawv (DEGs) ntawm V. harveyi kho thiab tsis kho. tus kab mob plees. Los ntawm cov ntaub ntawv sib sib zog nqus, peb tau txheeb xyuas 145 cov noob caj ces thiab 280 cov noob caj noob ces (Daim duab 1A). Ntawm lub hauv paus no, peb xaiv 10 qhov loj tshaj plaws thiab 10 qhov tsawg kawg nkaus DEGs (log2 ntawm kev hloov pauv yog 1.0) rau kev sib koom ua ke ntawm daim ntawv qhia, thiab cov txiaj ntsig tau pom tias cov qauv sib txawv hauv ob qho tib si V. harveyi kho thiab tsis kho cov qauv tau zoo dua (Daim duab 1B) . ACKR4a mRNAs tau tshuaj xyuas thiab pom tias nws tau hais tawm hauv M suab paj nruag lub hlwb tom qab V. harveyi kab mob (Daim duab S1A). Yog li M. muiiy hlwb kab (MBrC) tau siv rau kev sim tom ntej. Lub knockdown efficiency ntawm ACKR4a-si1 yog 46.1% thiab ACKR4a-si2 yog 63.7% hauv MBrC (Daim duab S1B), yog li ACKR4a-si2 (lub npe ACKR4a-si) tau siv rau kev sim tom ntej. Tom qab ntawd, peb tau tsom mus rau cov noob ACKR4a, uas tej zaum yuav muaj kev tiv thaiv kab mob, thiab cov qhab-nees-forming units (CFU) tau qhia tias ACKR4a txhawb V. harveyi proliferation (Figures 1C, 1D, thiab S1C). Txhawm rau tshawb xyuas ntxiv cov txheej txheem uas ACKR4a txhawb nqa V. harveyi proliferation, cov qauv qhia ntawm ACKR4a tau txheeb xyuas. ACKR4a hauv MBrC hlwb raug tswj los ntawm V. harveyi. Cov txiaj ntsig tau pom lub sijhawm nyob ntawm tus kab mob V. harveyi ntawm ob qho tib si mRNA thiab protein ntau (Figures 1E thiab 1F). Tsis tas li ntawd, ACKR4a silencing tau zoo txo cov kev qhia ntawm ACKR4a ntawm ob qho tib si mRNA thiab protein ntau (Figures 1E thiab 1G). Cov txiaj ntsig saum toj no tau qhia tias kev txhim kho ntawm ACKR4a tuaj yeem pab txhawb V. harveyi kab mob.
Daim duab 1. V. harveyi-induced ACKR4a txhawb nws txoj kev loj hlob
ACKR4a inhibits V. harveyi-triggered NF-kB signaling
Peb pom tias tus nqi ntawm cov cell proliferation tau cuam tshuam thaum MBrC tau kis tus kab mob V. harveyi, thiab los xyuas qhov kev tshawb pom no peb tau ua cov tshuaj ntsuam xyuas cell proliferation. Cov txiaj ntsig tau pom tias tus kab mob V. harveyi tau txo qis kev loj hlob ntawm MBrC (Daim duab S1D). Cov kev sim tom ntej tau lees paub tias ACKR4a dhau ntawm kev qhia txo qis ntawm cov cell proliferation, whereas ACKR4a silencing enhanced cell proliferation (Daim duab 2A thiab S1E). Ntau qhov kev tshawb fawb tau pom tias kev ua haujlwm ntawm NF-kB txhawb kev loj hlob ntawm tes. Nws tau pom tias BAY 11-7082, tus inhibitor ntawm NF-kB, kuj tuaj yeem txo qhov kev loj hlob ntawm MBrC (Daim duab 2A thiab S1E). Zoo ib yam li cov ntawv tshaj tawm dhau los, 43 qhov nce ntawm NF-kB-luc tau cuam tshuam nrog V. harveyi tus kab mob nyob rau lub sijhawm (Daim duab S1F).
Daim duab 2. ACKR4a inhibits V. harveyi-triggered NF-kB signaling
Txhawm rau txiav txim siab ntxiv qhov cuam tshuam ntawm ACKR4a ntawm V. harveyi-triggered NF-kB signaling, ib qho kev soj ntsuam ntawm tus neeg sau xov xwm luciferase tau ua. ACKR4a inhibited V. harveyi- thiab LPS-triggered NF-kB luciferase kev ua; V. harveyi-triggered IL-1b thiab TNFa luciferase kev ua haujlwm kuj raug cuam tshuam los ntawm ACKR4a (Figures 2B-2D). Endogenous ACKR4a tau nyob ntsiag to kom lees paub nws lub luag haujlwm hauv kev tiv thaiv hauv lub cev. Tom qab ntawd cov qauv qhia ntawm p65 thiab pro-inflammatory cytokines (IL-1b thiab TNFa) tau tshawb pom ntxiv, ACKR4a silencing tau nce p65 mRNAs, IL-1b mRNAs, thiab TNFa mRNAs (Figures 2E–2G ). Cov txiaj ntsig hauv MLC thiab MKC kuj tau qhia tias ACKR4a tuaj yeem cuam tshuam NF-kB signaling (Figures S1G-S1J). Cov txiaj ntsig ELISA kuj zoo ib yam; ACKR4a silencing tau nce TNFa thiab ACKR4a overexpression inhibited TNFa (Daim duab 2H). Txhawm rau ntsuas qhov ua kom NF-kB, nws yog qhov tsim nyog los soj ntsuam daim ntawv txhais lus, uas yog phosphorylated NF-kB, thiab nws yog ib qho kev ntsuas ntawm NF-kB kev ua haujlwm ntawm cov hom phiaj. Ntawm stimulation ntawm NF-kB, p65 yog phosphorylated thiab nkag mus rau hauv lub nucleus los tswj cov transcription ntawm pro-inflammatory cytokines. Txhawm rau tshawb xyuas cov kev cai ntawm p65 phosphorylation los ntawm ACKR4a, peb ntsuas phosphorylation theem ntawm p65 tom qab ACKR4a silencing thiab ACKR4a-overexpression los ntawm immunoblot. V. harveyi kab mob txhim kho p65 phosphorylation, uas ua pov thawj tias V. harveyi tau txais txiaj ntsig zoo NF-kB. Raws li qhov no, ACKR4a silencing txhim kho p65 phosphorylation, thaum ACKR4a-overexpression txo qis p65 phosphorylation, qhia tias ACKR4a yog ib qho inhibitor ntawm NF-kB signaling (Figures 2I thiab 2J). Hauv zebrafish, knockdown ntawm ACKR4a nce phosphorylation ntawm p65. Tsis tas li ntawd, qhov kev ntsuam xyuas CFU tau pom BAY 11-7082 tau nce qhov kev loj hlob ntawm MBrC (Daim duab 2K). Zuag qhia tag nrho, cov ntaub ntawv no qhia tias ACKR4a ua haujlwm raws li kev tswj hwm tsis zoo ntawm NF-kB teeb liab los tiv thaiv kev tiv thaiv kab mob hauv lub sijhawm V. harveyi kab mob.
Daim duab 3. ACKR4a cuam tshuam nrog MyD88 thiab txhawb nqa MyD88 degradation hauv autophagy
ACKR4a cuam tshuam nrog MyD88 thiab txhawb nqa MyD88 rau autophagic degradation
Tom ntej no, peb nrhiav kev los txiav txim siab seb lub hom phiaj twg hauv NF-kB teeb liab kev kho kom haum xeeb ACKR4a0 qhov kev txwv tsis pub muaj nuj nqi. NF-kB-luciferase reporter assay qhia tias overexpression ntawm ACKR4a ua rau txo qis ntawm luciferase kev ua, uas yog induced los ntawm MyD88 nyob rau hauv ib tug npaum li cas ntawm koob tshuaj (Daim duab 3A). Txawm li cas los xij, dhau qhov kev qhia ntawm ACKR4a tsis pom muaj kev cuam tshuam rau kev ua haujlwm ntawm luciferase uas tau tsav los ntawm TRAF6 lossis TAK1 (Figures 3B thiab 3C). Qhov tshwm sim ntawm immunoblot zoo ib yam li qhov kev ntsuam xyuas tus neeg sau xov xwm luciferase; overexpression ntawm ACKR4a inhibited MyD88 nyob rau hauv ib koob tshuaj, tab sis tsis muaj kev cuam tshuam rau TRAF6 thiab TAK1 (Daim duab 3D). Cov txiaj ntsig no qhia tias ACKR4a ua haujlwm ntawm MyD88 qib.
Tag nrho cov tsiaj nyeg TLRs, tshwj tsis yog TLR3, nyob ntawm tsawg kawg yog ib feem ntawm MyD88 adapter xa cov cim, uas ua rau kev tswj hwm ncaj qha ntawm MyD88 zoo dua.44 Peb mam li tshuaj xyuas cov lus qhia ntawm MyD88 ntawm lub sijhawm sib txawv ntawm tus kab mob V. harveyi thiab pom ACKR4a ntsiag to. txhim kho qhov kev qhia ntawm MyD88 (Daim duab 3E), thiab ACKR4a-overexpression inhibited MyD88 kev qhia nyob rau lub sijhawm (Daim duab 3F). Ib qho txiaj ntsig zoo tau pom tias txawm hais tias ACKR4a silencing txhim kho MyD88 kev qhia tshwm sim los ntawm V. harveyi, qhov kev txhim kho no tsis tshwm sim thaum lub hlwb tau so (Daim duab 3G thiab 3H). Txhawm rau kom nkag siab zoo dua cov txheej txheem molecular hauv qab qhov kev txiav txim ntawm ACKR4a hauv MyD88- kho NF-kB kev taw qhia, peb tau ua qhov kev ntsuam xyuas Co-immunoprecipitation (Co-IP) los txiav txim seb ACKR4a cuam tshuam nrog MyD88. Flag-ACKR4a tuaj yeem tiv thaiv kab mob nrog Myc-MyD88 (Figures 3I thiab S1K). Raws li qhov ntawd, peb pom tias Flag-MyD88 tuaj yeem cuam tshuam nrog endogenous ACKR4a (Daim duab 3J). Cov kev sim tom qab subcellular localization tau pom tias ACKR4a tsis muaj qhov tseem ceeb ntawm kev sib koom ua ke nrog MyD88 (Daim duab S1L). Yog li, cov kev tshawb pom no txhawb lub tswv yim tias ACKR4a lub cev cuam tshuam nrog MyD88, thiab lawv cov kev sib cuam tshuam yuav tshwm sim hauv cytoplasm. Tom ntej no, peb tshawb xyuas cov txheej txheem uas ACKR4a suppressed MyD88 qhia. Ob leeg NH4Cl los yog 3-Methyladenine (3-MA), inhibitors ntawm autophagy-lysosome-degradation txoj kev, ua rau muaj kev cuam tshuam loj ntawm MyD88 nyob rau hauv lub xub ntiag ntawm ACKR4a, thiab MG132 tsis cuam tshuam rau kev degradation ntawm MyD88 (Daim duab 3K). Ntxiv mus, cov txiaj ntsig zoo sib xws tau pom tias 3-MA thiab NH4Cl cuam tshuam MyD88 degradation nyob rau hauv cov koob tshuaj (Daim duab 3L thiab 3M). Cov kev tshawb pom no zoo li qhia tau hais tias thaiv qhov autophagy zoo tiv thaiv ACKR4a-targeted MyD88 degradation. Autophagic flux qhia txog cov txheej txheem dynamic ntawm autophagy, uas yog ib qho kev txhim khu kev qha ntawm kev ua haujlwm autophagic. Vim tias GFP fluorescence yog quenched hauv lysosome, theem ntawm autophagy tuaj yeem txiav txim siab los ntawm fluorescence ntawm GFP thiab RFP.42 Kev soj ntsuam ntawm cov fluorescence daj nyob rau hauv Merge vaj huam sib luag pom ntau cov fluorescence liab nyob rau hauv lub xub ntiag ntawm ACKR4a, qhia ACKR4a txhawb kev fusion ntawm autophagosomes thiab lysosomes; whereas lub autophagy inhibitor chloroquine (CQ) tiv thaiv fusion ntawm autophagosomes thiab lysosomes, qhia ntau daj fluorescence (Daim duab 3N). Txhawm rau kom ntseeg tau ntxiv tias ACKR4a lub hom phiaj MyD88 rau autophagic degradation, qhov kev ntsuam xyuas lysosomal localization tau ua, MyD88 (ntsuab) thiab lysosomes (liab) tau sib koom ua ke hauv MBrC cell (Daim duab 3O), qhia tias MyD88 raug thauj mus rau lysosomes. Ua ke, cov txiaj ntsig no qhia tias ACKR4a cuam tshuam nrog MyD88 thiab tsom mus rau MyD88 rau autophagic degradation.
Daim duab 4. ACKR4a koom nrog kev tswj hwm ntawm autophagy ntawm Beclin-1
ACKR4a koom nrog kev tswj hwm ntawm autophagy ntawm Beclin-1
Qee cov kab mob siv autophagy los txhawb lawv txoj kev loj hlob thiab kev kis kab mob, lawv cov kev rov ua dua tshiab yuav raug txo kom tsawg thaum autophagy tsis tuaj.13 Txhawm rau kuaj seb V. harveyi koom nrog kev tswj hwm ntawm autophagy hauv MBrC hlwb, cov hlwb tau kis tus kab mob V. harveyi thiab tom qab ntawd cov qauv qhia. ntawm LC3 tau tshuaj xyuas. Nyob rau hauv MBrC hlwb, V. harveyi raug nce autophagy raws li qhia los ntawm tsub zuj zuj ntawm GFP-LC3 puncta, uas tau nrog lub sij hawm-nyob ntawm qhov nce ntawm V. harveyi kab mob (Daim duab 4A). ACKR4a overexpression enhanced V. harveyi-induced autophagy raws li qhia los ntawm ib tug zoo kawg li nce nyob rau hauv puncta accumulations ntawm RFP-LC3, nyob rau hauv sib piv rau ACKR4a silencing uas txo V. harveyi-induced autophagy (Figures 4B thiab 4C). Tsis tas li ntawd, ACKR4a silence ua rau txo qis hauv V. harveyi-induced LC3-II qhia (Daim duab 4D).
ULK1, Beclin-1, thiab ATG5 yog cov txheej txheem tswj hwm tseem ceeb ntawm autophagy. qPCR cov txiaj ntsig tau pom tias ACKR4a tau txhim kho qhov kev qhia ntawm Beclin-1, tab sis tsis yog ULK1 thiab ATG5 (Daim duab 4E). Qhov kev ntsuam xyuas luciferase ntawm ULK1, ATG5, thiab Beclin-1 tau qhia tias overexpression ntawm ACKR4a tsuas yog ua rau muaj kev nce ntawm Beclin-1luciferase kev ua (Daim duab 4F). Tom ntej no, peb tau tshawb pom tias qhov kev nthuav tawm ntau dhau ntawm ACKR4a txhim kho qhov kev qhia ntawm Beclin-1, tab sis tsis yog ULK1 thiab ATG5 (Daim duab 4G). Tsis tas li ntawd, ACKR4a-induced autophagy yog inhibited los ntawm Beclin{21}}si, whereas ATG5-si tsuas muaj ib feem inhibition (Daim duab 4H). Cov txiaj ntsig saum toj no tau qhia tias ACKR4a tau tsom mus rau Beclin-1. Yog li ntawd, txoj haujlwm thiab cov txheej txheem ntawm Beclin-1 hauv ACKR4a-mediated autophagic degradation ntawm MyD88 tau tshawb xyuas. Hauv zebrafish kis nrog V. harveyi, knockdown ntawm ACKR4a tsis ua rau muaj kev hloov pauv loj hauv ULK1 thaum txo qis Beclin-1 thiab ATG5 (Figures S2B-S2D). Beclin-1 ntxiv txhim kho ACKR4a-induced autophagic flux nrog Baf1A thiab CQ kho (Daim duab 4I), thiab Beclin-1 txhim kho qhov degradation ntawm MyD88 los ntawm ACKR4a (Daim duab 4J). Peb mam li ua qhov kev ntsuam xyuas Co-IP los txiav txim seb ACKR4a cuam tshuam nrog Beclin-1, thiab pom tias ACKR4a cuam tshuam nrog Beclin-1, thiab V. harveyi kab mob txhim kho kev sib cuam tshuam ntawm ACKR4a thiab Beclin{{51 }} (Daim duab 4K). Kev ntsuam xyuas lysosomal localization qhia tias ACKR4a txhim kho lub autophagosome fuse nrog lysosome (Daim duab 4L). Tom qab ntawd, ACKR4a nce endogenous Beclin-1 qhia (Daim duab 4M) thiab ACKR4a silencing attenuates V. harveyi-induced Beclin-1 qhia (Daim duab 4N). Tsis tas li ntawd, Beclin-1 silencing txhim kho cov phosphorylation ntawm p65 tshwm sim los ntawm V. harveyi, uas ntxiv qhia tias V. harveyi induces autophagy kom tsis zoo tswj NF-kB signaling (Daim duab 4O). Peb tom ntej no nrhiav kev txiav txim siab txog kev lom neeg ntawm Beclin-1 hauv kev kis tus kab mob V. harveyi, tshwj xeeb hauv kev tswj hwm V. harveyi proliferation. Kev soj ntsuam CFU tau ua tiav thiab pom ob qho tib si Beclin-1 silencing thiab CQ-blocked autophagy txo qhov kev loj hlob ntawm V. harveyi, uas ua pov thawj tias V. harveyi siv autophagy los txhawb nws txoj kev loj hlob (Daim duab 4P). Cov txiaj ntsig saum toj no ua ke qhia tias ACKR4a induces thiab form complexes nrog Beclin-1 los txhawb autophagy, thiab ces pab txhawb V. harveyi kab mob.
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ACKR4a induced autophagy rau thaiv apoptosis
Autophagic cell tuag yog suav tias yog ib qho tsim nyog lwm txoj rau apoptosis, thiab apoptosis kuj yog ib qho kev paub txog kev siv tshuaj tua kab mob; Kev ua tiav cov kab mob ua kom tiav tus kheej rov ua dua los ntawm inhibiting apoptosis.22 Txhawm rau txiav txim siab txog kev sib raug zoo ntawm V. harveyi-induced autophagy thiab apoptosis, apoptosis ntawm MBrC hlwb nrog kev kho mob sib txawv ua ntej thiab tom qab V. harveyi kab mob tau txiav txim siab, thiab ACKR4a silencing nce V. harveyi-induced apoptosis (Figures 5A thiab 5B, sab laug vaj huam sib luag). Vim tias caspase3 thiab caspase7 yog qhov tseem ceeb hauv kev pib ntawm apoptosis, lawv tau txais dav raws li qhov ntsuas pom tseeb ntawm apoptosis. Kev ntsuam xyuas caspase Glo 3/7 tau pom tias ACKR4a overexpression inhibited V. harveyi-induced caspase3/7 kev ua haujlwm, whereas ACKR4a silencing enhanced V. harveyi-induced caspase3/7 kev ua (Daim duab 5B, txoj cai vaj huam sib luag). V. harveyi thiab exogenously ntxiv recombinant active caspase8 induced caspase3/7 kev ua ub no yog inhibited los ntawm ACKR4a (Daim duab 5C), qhia tias ACKR4a muaj peev xwm ua tau zoo thaiv cov teeb liab apoptosis. Txawm hais tias ACKR4a-induced autophagy tau tshwm sim, xav tau kev tshawb fawb ntxiv los tshawb xyuas lub luag haujlwm ntawm autophagy hauv kev thaiv apoptosis. Raws li pom nyob rau hauv daim duab 5D ACKR4a silencing ho nce lub effector caspases (caspase7) thiab cov initiator caspases (caspase8). Tsis tas li ntawd, ACKR4a overexpression inhibited caspase7 thiab caspase8 mRNAs (Daim duab 5E) thiab ACKR4a knockdown ho nce caspase7 thiab caspase8 hauv zebrafish (Figures S2E thiab S2F). Cov kev tshawb fawb yav dhau los tau pom tias Beclin-1 yog qhov hloov pauv molecular uas kho cov txheej txheem apoptosis thiab autophagy, 45 yog li kev koom tes ntawm Beclin-1 hauv kev tswj hwm ntawm apoptosis tau tshawb nrhiav. Hauv peb txoj kev tshawb fawb, Beclin-1 overexpression down-regulated V. harveyi-induced caspase8, whereas Beclin-1 silencing up-regulated V. harveyi-induced caspase8 (Daim duab 5F). Ib qho txiaj ntsig zoo tau pom tias caspase8 tau nce siab heev ntawm 3 h ntawm V. harveyi kab mob; nws tau rov inhibited nrog lub sijhawm ntawm kev kis tus kabmob, thiab LC3-II tau cuam tshuam tsis zoo nrog caspase8 (Daim duab 5G). Raws li cov txiaj ntsig saum toj no, ACKR4a induced autophagy los thaiv apoptotic signaling thiab pab txhawb V. harveyi kab mob, thiab Beclin-1 tej zaum yuav yog lub hom phiaj muaj peev xwm nyob rau hauv cascade ntawm autophagy thiab apoptosis.
Daim duab 5. ACKR4a induces autophagy los thaiv apoptosis
Ap-1 txhim kho ACKR4a-induced autophagy ntawm V. harveyi kab mob
Tom qab ntawd, cov txheej txheem ntawm V. harveyi kab mob tshwm sim ACKR4a qhia tau raug tshawb xyuas. Plaub qhov sib txawv ACKR4a txhawb nqa plasmids tau tsim ua ntej raws li cov kev kwv yees ua ntu zus (Daim duab 6A). Qhov kev ntsuam xyuas luciferase tau pom tias ACKR4a-p-3 kev ua haujlwm yog qhov siab tshaj plaws (Daim duab 6B). Txhawm rau txheeb xyuas cov kab hluav taws xob ntws tawm ntawm ACKR4a qhia thaum lub sij hawm V. harveyi kab mob, thaj tsam txhawb nqa ntawm ACKR4a tau txheeb xyuas, thiab pom tias ACKR4a muaj peev xwm khi qhov chaw ntawm Sp-1 thiab Ap-1 (Daim duab 6C). Qhov kev ntsuam xyuas ACKR4a-luc tau qhia tias Sp-1 tsis tuaj yeem txhim kho cov kev ua haujlwm ntawm luciferase thiab Ap-1 txhim kho kev ua haujlwm ntawm luciferase (Figures 6D thiab 6E), uas tau tsa qhov muaj peev xwm uas ACKR4a tuaj yeem yog lub hom phiaj ncaj qha ntawm Ap -1. Txhawm rau tshuaj xyuas qhov no, ob lub luciferase vectors uas muaj cov mutant ACKR4a tau tsim (Daim duab 6F). Qhov kev ntsuam xyuas luciferase tau pom tias cov mutants tsis muaj Ap-1 cov chaw sib txuas tau cuam tshuam cov kev ua ntawm luciferase qhov sib piv rau hom tsiaj qus (Daim duab 6G). Txhawm rau kom paub meej tias Ap-1 txhawb nqa ACKR4a kev qhia, peb tau ntsiag to lossis txhim kho qhov kev qhia ntawm Ap-1 dhau ntawm kev nthuav tawm lossis knockdown, thiab ACKR4a qhia tau raug soj ntsuam hauv cov kab mob MBrC. Ap-1 silencing txo qis V. harveyi-induced ACKR4a qhia (Daim duab 6H), hos Ap-1 overexpression ho txhim kho ACKR4a qhia (Daim duab 6I). Cov txiaj ntsig ntawm immunoblot tau ua raws li cov txiaj ntsig ntawm qPCR, Ap-1 overexpression tau nce qhov kev qhia ntawm ACKR4a, thaum Ap{40}} silencing txo qhov kev qhia ntawm ACKR4a (Daim duab 6J). Chip tsom xam pom tias Ap-1 khi rau ACKR4a txhawb nqa hauv MBrC hlwb nyob rau hauv ib txwm muaj lub cev muaj zog, thiab V. harveyi stimulation txhim kho qhov khi ntawm Ap-1 rau ACKR4a txhawb nqa (Daim duab 6K). Cov txiaj ntsig saum toj no tau lees paub tias ACKR4a yog lub hom phiaj muaj peev xwm hloov pauv ntawm Ap-1. Txoj haujlwm ntawm Ap-1 hauv autophagy tau tshawb nrhiav; Ap-1 silencing ua tau zoo txo qhov V. harveyi kab mob-induced tsub zuj zuj ntawm GFP-LC3 (Daim duab 6L), thiab nws kuj attenuated V. harveyi kab mob-induced up-regulation ntawm LC3-II (Daim duab 6M ). Kev soj ntsuam CFU tau ua los tshawb nrhiav lub luag haujlwm ntawm Ap-1 hauv V. harveyi tus kab mob thiab pom tias AP-1 txhawb nqa V. harveyi proliferation (Daim duab 6N). Ua ke, cov txiaj ntsig saum toj no tau qhia tias Ap-1 qhib ACKR4a cov ntawv sau thiab qhia thiab pab txhawb rau tus kab mob V. harveyi.
Daim duab 6. Ap-1 txhim kho ACKR4a induced autophagy ntawm V. harveyi kab mob
Daim duab 7. Tus qauv ua hauj lwm ntawm yuav ua li cas ACKR4a pab txhawb V. harveyi kab mob
Kev sib tham
ACKRs tau pom tias muaj kev koom tes hauv ntau cov txheej txheem lom neeg xws li kev tswj hwm kev tswj hwm, chemokine ligand internalization, intracellular degradation, thiab inflammatory teb, 4,26 uas yog ib qho tseem ceeb tsis yog rau kev tiv thaiv kab mob xwb tab sis kuj yog ib qho tseem ceeb ntawm lub cev tiv thaiv kab mob. .33,34 Txawm li cas los xij, lub luag haujlwm ntawm ACKRs hauv cov lus teb rau cov kab mob hauv cov ntses tsis tau tshawb xyuas. Txoj kev tshawb no nthuav tawm thawj zaug uas ACKR4a, tus tswv cuab ntawm ACKR tsev neeg, txhawb nqa tus kab mob V. harveyi rau teleost ntses los ntawm autophagy thiab apoptosis. Mechanistically, qhov kev hloov pauv ntawm ACKR4a tau tswj hwm los ntawm qhov hloov pauv hloov pauv AP-1. Tom qab ntawd cov txheej txheem tswj hwm ACKR4a tau koom ua ke nrog Beclin{10}} txhawm rau ua kom tsis muaj zog thiab thauj MyD88 mus rau lysosomes rau kev puas tsuaj. Lub caij no, ACKR4a induces autophagy los thaiv apoptosis thiab tom qab ntawd pab txhawb V. harveyi kab mob (Daim duab 7). Innate immunity plays lub luag haujlwm tseem ceeb hauv kev tiv thaiv eukaryotes los ntawm endogenous thiab exogenous pathogenic invasion.46 Raws li qhov tshwm sim ntawm cov kab mob mus ntev, cov ntses tau hloov zuj zus ntxiv kev tiv thaiv innate los tiv thaiv lawv ntawm kev kis kab mob.47 TLRs lees paub PAMP thaum muaj kab mob tshwm sim, thiab pib lub cev tiv thaiv kab mob hauv lub cev los ntawm MyD88- txoj hauv kev nyob thiab ywj pheej, uas ua rau tsim cov cytokines pro-inflammatory los tshem tawm cov kab mob. MyD88 yog ib qho tseem ceeb adapter hauv TLR signaling, tshwj tsis yog TLR3, tag nrho cov tsiaj nyeg TLRs siv MyD88 los qhib NF-kB signaling.48 Yog li ntawd, nws yuav yog qhov zoo tshaj plaws los tswj MyD88 ncaj qha. Piv txwv li, S-1-acetylcysteine inhibits IL-6 ntau lawm los ntawm inducing degradation ntawm MyD88. Ib yam li ntawd, hauv cov ntses, IRF3 thiab eIF3k tau tshaj tawm tias inhibit NF-kB signaling los ntawm kev tsom mus rau MyD88.42,49 Cov pov thawj tseem ceeb tau qhia tias MyD88 tseem ceeb rau kev tshem tawm cov kab mob. Piv txwv li, MyD88-cov nas uas tsis muaj peev xwm tsis paub txog cov kab mob sib kis thiab muaj feem cuam tshuam rau S. aureus. 50 Tsis tas li ntawd, MyD88 kuj tau pom tias muaj kev koom tes hauv kev tshem tawm cov kab mob kab mob hauv cov ntses zebrafish.41 Kev ua kom lub cev tiv thaiv kab mob hauv lub cev txhawb nqa cov kab mob tshem tawm, uas ua rau muaj kev xaiv loj, txhawb lawv kom hloov tau lub peev xwm los tiv thaiv kev tiv thaiv innate. .51,52 Nws tau raug pom tias salmonella tuaj yeem tswj cov kab mob tiv thaiv kab mob thiab tswj cov kab mob inflammatory tom qab kis tus tswv tsev. Tus kab mob salmonella virulence SpvC irreversibly dephosphorylates ERK, p38, thiab MAPK, yog li inhibiting cov transcription ntawm pro-inflammatory cytokines.53 Nyob rau hauv txoj kev tshawb no, up-regulated ACKR4a nyob rau hauv V. harveyi-mob M. miiuy tau ua ke nrog MyD58pho inhibit pry6. thiab thaiv NF-kB signaling. Qhov no qhia tau hais tias cov kab mob tuaj yeem cuam tshuam lub cev tiv thaiv kab mob hauv cov ntses los ntawm kev cuam tshuam nrog kev ruaj ntseg ntawm cov adapters hauv TLR signaling rau lub hom phiaj ntawm kev tiv thaiv kab mob.
Autophagy thiab apoptosis yog ob lub tswv yim pom zoo ntawm kev tiv thaiv kab mob ntxeem tau, nrog rau cov tshuaj tua kab mob autophagy yog ib qho thaiv tiv thaiv kab mob invading. PRRs tuaj yeem ua rau autophagy ntawm ntau theem ntawm tus tswv-tus kab mob sib cuag, thiab inhibit qhov kev loj hlob ntawm cov kab mob hauv lub cev.54 Hloov pauv, cov kab mob kuj tau hloov kho cov txheej txheem zoo los tiv thaiv, sib ntaus sib tua, lossis hais kom autophagy. Cov txheej txheem no feem ntau koom nrog kev tsom mus rau Beclin-1 txhawm rau thaiv autophagy,55 tiv thaiv kev loj hlob ntawm autophagosomes56 thiab txawm tias ua kom autophagy hauv qee kis los muab khoom noj rau cov kab mob loj hlob.57 Qhov txawv, peb pom tias V. harveyi ntxias Beclin{{6} } qhib autophagy ntawm ACKR4a, uas yog lub hom phiaj MyD88 rau autophagic degradation, yog li thaiv NF-kB signaling thiab txhawb nqa tus kheej-replication. Lwm lub tswv yim tiv thaiv yog programmed cell tuag (apoptosis), uas yog qhib thaum cov kab mob siv cov cell ua kom muaj sia nyob thiab rov ua dua. Piv txwv li, mycobacterium kab mob ntawm macrophages ua rau apoptosis, uas pab txhawb kev tshem tawm cov kab mob ntawm cov cell.58 Ntxiv rau, TNF-a-mediated macrophage apoptosis rhuav tshem cov chaw intracellular rau mycobacterium replicates thiab txo qhov kev loj hlob ntawm tus kab mob mycobacterium.59 Los tiv thaiv. Kev muaj sia nyob siab ntawm apoptosis, ntau cov kab mob ua tau zoo encode cov noob uas nws cov khoom inhibit apoptosis hauv cov hlwb, yog li tswj cov kev muaj peev xwm ntawm cov kab mob sib txuas. Hauv peb txoj kev tshawb fawb, V. harveyi-induced autophagy plays lub luag haujlwm hauv cov theem apoptotic thiab blocks apoptotic signaling. Apoptosis thiab autophagy ob leeg txhawb thiab tawm tsam ib leeg. Hauv cov theem ua ntej apoptotic, cov hlwb thaiv txoj hauv kev apoptotic thiab txo cov theem ntawm apoptosis los ntawm autophagy, yog li tswj kom zoo dua. Autophagy tsis ua rau cov cell tuag nyob rau hauv cov theem pib ntawm apoptosis tab sis kuj txhawb cell ciaj sia.61 Autophagy thaum lub sij hawm lig theem ntawm apoptosis yuav txhawb apoptosis, thiab tom qab ntawd nce apoptosis inhibits qhov tshwm sim ntawm autophagy los ntawm kev tsiv teb tsaws ntawm p53 thiab BH3 pathways.62 Cov txheej txheem lom neeg raug tswj nruj, suav nrog kev cuam tshuam ntawm autophagy thiab apoptosis. Ntau yam kev tswj hwm cov noob tau koom nrog hauv kev sib cuam tshuam cov txheej txheem ntawm apoptosis thiab autophagy, Beclin-1 yog ib qho ntawm lawv.63 Ntxiv rau cov kev cai ntawm kev pib autophagy, Beclin-1 kuj koom nrog hauv kev tswj hwm apoptosis.45 ,64 Kev tshawb fawb tau pom tias Beclin-1 poob nws lub peev xwm los tiv thaiv apoptosis tom qab tau cleaved los ntawm activated caspases.65 Qhov no qhia tias Beclin-1 plays lub luag hauj lwm tseem ceeb raws li "molecular hloov" nyob rau hauv cov kev cai autophagy thiab apoptosis.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
V. harveyi yog cov kab mob marine gram-negative uas ua rau muaj kev hem thawj rau kev noj qab haus huv ntawm marine aquaculture fisheries. V. harveyi kab mob ua rau mob meningitis thiab encephalitis nyob rau hauv cov ntses, 66 thiab V. harveyi kab mob ua rau cerebral congestion nyob rau hauv grouper.67 Nyob rau hauv teb rau cov kab mob, lub innate tiv thaiv kab mob thiab inflammatory teb yog lub ntsiab tiv thaiv kab mob ntawm cov ntses. Txawm li cas los xij, cov kab mob kuj tau hloov kho lub peev xwm los tiv thaiv kev tiv thaiv hauv symbiosis nrog lawv cov tswv. Hauv cov ntsiab lus, peb cov txiaj ntsig tau nthuav tawm cov txheej txheem ntawm V. harveyi tiv thaiv kab mob hauv cov ntses. ACKR4a induces autophagy los inhibit NF-kB signaling thiab thaiv apoptosis, uas nyob rau hauv lem pab txhawb V. harveyi kab mob nyob rau hauv teleost ntses. Qhov no kuj yog thawj zaug uas cov kab mob gram-tsis zoo tau pom los ntawm kev tiv thaiv kab mob los ntawm ib txhij tswj kev tiv thaiv kab mob hauv lub cev thiab apoptosis ntawm autophagy. Txoj kev tshawb no muab kev nkag siab txog kev nkag siab txog qhov cuam tshuam ntawm autophagy ntawm tus tswv tsev-cov kab mob sib cuam tshuam hauv cov ntses teleost thiab muab kev pom ntawm cov tsiaj txhu tiv thaiv kab mob.
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