Inhibition of SIRT2 promotes death of human cytomegalovirus-infected peripheral blood monocytes via apoptosis and necroptosis
Copyright © 2023 Elsevier B.V. All rights reserved..
Peripheral blood monocytes are the cells predominantly responsible for systemic dissemination of human cytomegalovirus (HCMV) and a significant cause of morbidity and mortality in immunocompromised patients. HCMV establishes a silent/quiescent infection in monocytes, which is defined by the lack of viral replication and lytic gene expression. The absence of replication shields the virus within infected monocytes from the current available antiviral drugs that are designed to suppress active replication. Our previous work has shown that HCMV stimulates a noncanonical phosphorylation of Akt and the subsequent upregulation of a distinct subset of prosurvival proteins in normally short-lived monocytes. In this study, we found that SIRT2 activity is required for the unique activation profile of Akt induced within HCMV-infected monocytes. Importantly, both therapeutic and prophylactic treatment with a novel SIRT2 inhibitor, FLS-379, promoted death of infected monocytes via both the apoptotic and necroptotic cell death pathways. Mechanistically, SIRT2 inhibition reduced expression of Mcl-1, an Akt-dependent antiapoptotic Bcl-2 family member, and enhanced activation of MLKL, the executioner kinase of necroptosis. We have previously reported HCMV to block necroptosis by stimulating cellular autophagy. Here, we additionally demonstrate that inhibition of SIRT2 suppressed Akt-dependent HCMV-induced autophagy leading to necroptosis of infected monocytes. Overall, our data show that SIRT2 inhibition can simultaneously promote death of quiescently infected monocytes by two distinct death pathways, apoptosis and necroptosis, which may be vital for limiting viral dissemination to peripheral organs in immunosuppressed patients.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:217 |
|---|---|
| Enthalten in: |
Antiviral research - 217(2023) vom: 09. Sept., Seite 105698 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Cheung, Jennifer [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 29.08.2023 Date Revised 29.08.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.antiviral.2023.105698 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM360621813 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM360621813 | ||
| 003 | DE-627 | ||
| 005 | 20231226083414.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.antiviral.2023.105698 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1202.xml |
| 035 | |a (DE-627)NLM360621813 | ||
| 035 | |a (NLM)37562606 | ||
| 035 | |a (PII)S0166-3542(23)00176-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Cheung, Jennifer |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of SIRT2 promotes death of human cytomegalovirus-infected peripheral blood monocytes via apoptosis and necroptosis |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.08.2023 | ||
| 500 | |a Date Revised 29.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a Peripheral blood monocytes are the cells predominantly responsible for systemic dissemination of human cytomegalovirus (HCMV) and a significant cause of morbidity and mortality in immunocompromised patients. HCMV establishes a silent/quiescent infection in monocytes, which is defined by the lack of viral replication and lytic gene expression. The absence of replication shields the virus within infected monocytes from the current available antiviral drugs that are designed to suppress active replication. Our previous work has shown that HCMV stimulates a noncanonical phosphorylation of Akt and the subsequent upregulation of a distinct subset of prosurvival proteins in normally short-lived monocytes. In this study, we found that SIRT2 activity is required for the unique activation profile of Akt induced within HCMV-infected monocytes. Importantly, both therapeutic and prophylactic treatment with a novel SIRT2 inhibitor, FLS-379, promoted death of infected monocytes via both the apoptotic and necroptotic cell death pathways. Mechanistically, SIRT2 inhibition reduced expression of Mcl-1, an Akt-dependent antiapoptotic Bcl-2 family member, and enhanced activation of MLKL, the executioner kinase of necroptosis. We have previously reported HCMV to block necroptosis by stimulating cellular autophagy. Here, we additionally demonstrate that inhibition of SIRT2 suppressed Akt-dependent HCMV-induced autophagy leading to necroptosis of infected monocytes. Overall, our data show that SIRT2 inhibition can simultaneously promote death of quiescently infected monocytes by two distinct death pathways, apoptosis and necroptosis, which may be vital for limiting viral dissemination to peripheral organs in immunosuppressed patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Cytomegalovirus | |
| 650 | 4 | |a Monocyte | |
| 650 | 4 | |a Necroptosis | |
| 650 | 4 | |a Sirtuin 2 | |
| 650 | 4 | |a Small-molecule inhibitor | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Sirtuin 2 |2 NLM | |
| 650 | 7 | |a EC 3.5.1.- |2 NLM | |
| 650 | 7 | |a SIRT2 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.5.1.- |2 NLM | |
| 700 | 1 | |a Remiszewski, Stacy |e verfasserin |4 aut | |
| 700 | 1 | |a Chiang, Lillian W |e verfasserin |4 aut | |
| 700 | 1 | |a Ahmad, Ejaz |e verfasserin |4 aut | |
| 700 | 1 | |a Pal, Mohan |e verfasserin |4 aut | |
| 700 | 1 | |a Rahman, Sm Ashikur |e verfasserin |4 aut | |
| 700 | 1 | |a Nikolovska-Coleska, Zaneta |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Gary C |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Antiviral research |d 1983 |g 217(2023) vom: 09. Sept., Seite 105698 |w (DE-627)NLM012601756 |x 1872-9096 |7 nnns |
| 773 | 1 | 8 | |g volume:217 |g year:2023 |g day:09 |g month:09 |g pages:105698 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.antiviral.2023.105698 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 217 |j 2023 |b 09 |c 09 |h 105698 | ||