A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.

TRIM5α is a key cross-species barrier to retroviral infection, with certain TRIM5 alleles conferring increased risk of HIV-1 infection in humans. TRIM5α is best known as a species-specific restriction factor that directly inhibits the viral life cycle. Additionally, it is also a pattern-recognition...

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Autores principales:	Bhaskar Saha, Devon Chisholm, Alison M Kell, Michael A Mandell
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2020
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d8319a2ceeae4321ab676ebe44cf7a7e
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spelling	oai:doaj.org-article:d8319a2ceeae4321ab676ebe44cf7a7e2021-12-02T20:00:18ZA non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.1553-73661553-737410.1371/journal.ppat.1009017https://doaj.org/article/d8319a2ceeae4321ab676ebe44cf7a7e2020-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009017https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374TRIM5α is a key cross-species barrier to retroviral infection, with certain TRIM5 alleles conferring increased risk of HIV-1 infection in humans. TRIM5α is best known as a species-specific restriction factor that directly inhibits the viral life cycle. Additionally, it is also a pattern-recognition receptor (PRR) that activates inflammatory signaling. How TRIM5α carries out its multi-faceted actions in antiviral defense remains incompletely understood. Here, we show that proteins required for autophagy, a cellular self-digestion pathway, play an important role in TRIM5α's function as a PRR. Genetic depletion of proteins involved in all stages of the autophagy pathway prevented TRIM5α-driven expression of NF-κB and AP1 responsive genes. One of these genes is the preeminent antiviral cytokine interferon β (IFN-β), whose TRIM5-dependent expression was lost in cells lacking the autophagy proteins ATG7, BECN1, and ULK1. Moreover, we found that the ability of TRIM5α to stimulate IFN-β expression in response to recognition of a TRIM5α-restricted HIV-1 capsid mutant (P90A) was abrogated in cells lacking autophagy factors. Stimulation of human macrophage-like cells with the P90A virus protected them against subsequent infection with an otherwise resistant wild type HIV-1 in a manner requiring TRIM5α, BECN1, and ULK1. Mechanistically, TRIM5α was attenuated in its ability to activate the kinase TAK1 in autophagy deficient cells, and both BECN1 and ATG7 contributed to the assembly of TRIM5α-TAK1 complexes. These data demonstrate a non-canonical role for the autophagy machinery in assembling antiviral signaling complexes and in establishing a TRIM5α-dependent antiviral state.Bhaskar SahaDevon ChisholmAlison M KellMichael A MandellPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 16, Iss 10, p e1009017 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Bhaskar Saha Devon Chisholm Alison M Kell Michael A Mandell A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.
description	TRIM5α is a key cross-species barrier to retroviral infection, with certain TRIM5 alleles conferring increased risk of HIV-1 infection in humans. TRIM5α is best known as a species-specific restriction factor that directly inhibits the viral life cycle. Additionally, it is also a pattern-recognition receptor (PRR) that activates inflammatory signaling. How TRIM5α carries out its multi-faceted actions in antiviral defense remains incompletely understood. Here, we show that proteins required for autophagy, a cellular self-digestion pathway, play an important role in TRIM5α's function as a PRR. Genetic depletion of proteins involved in all stages of the autophagy pathway prevented TRIM5α-driven expression of NF-κB and AP1 responsive genes. One of these genes is the preeminent antiviral cytokine interferon β (IFN-β), whose TRIM5-dependent expression was lost in cells lacking the autophagy proteins ATG7, BECN1, and ULK1. Moreover, we found that the ability of TRIM5α to stimulate IFN-β expression in response to recognition of a TRIM5α-restricted HIV-1 capsid mutant (P90A) was abrogated in cells lacking autophagy factors. Stimulation of human macrophage-like cells with the P90A virus protected them against subsequent infection with an otherwise resistant wild type HIV-1 in a manner requiring TRIM5α, BECN1, and ULK1. Mechanistically, TRIM5α was attenuated in its ability to activate the kinase TAK1 in autophagy deficient cells, and both BECN1 and ATG7 contributed to the assembly of TRIM5α-TAK1 complexes. These data demonstrate a non-canonical role for the autophagy machinery in assembling antiviral signaling complexes and in establishing a TRIM5α-dependent antiviral state.
format	article
author	Bhaskar Saha Devon Chisholm Alison M Kell Michael A Mandell
author_facet	Bhaskar Saha Devon Chisholm Alison M Kell Michael A Mandell
author_sort	Bhaskar Saha
title	A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.
title_short	A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.
title_full	A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.
title_fullStr	A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.
title_full_unstemmed	A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.
title_sort	non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by trim5α.
publisher	Public Library of Science (PLoS)
publishDate	2020
url	https://doaj.org/article/d8319a2ceeae4321ab676ebe44cf7a7e
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A non-canonical role for the autophagy machinery in anti-retroviral signaling mediated by TRIM5α.

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