Species‐specific impact of the autophagy machinery on Chikungunya virus infection

Judith, Delphine; Mostowy, Serge; Bouraï, Mehdi; Gangneux, Nicolas; Lelek, Mickaël; Lucas‐Hourani, Marianne; Cayet, Nadège; Jacob, Yves; Prévost, Marie‐Christine; Pierre, Philippe; Tangy, Frédéric; Zimmer, Christophe; Vidalain, Pierre‐Olivier; Couderc, Thérèse; Lecuit, Marc

doi:10.1038/embor.2013.51

Cited by 124 publications

(147 citation statements)

References 35 publications

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“…Although we cannot exclude modification of other residues or the involvement of unidentified cellular proteins belonging to the complex Tat/p62, our data represent the first demonstration of selective autophagic degradation of a viral transactivator. Indeed, in a context of viral infection, a selective p62-mediated degradation has been demonstrated only for two structural viral proteins, the capsid protein of the chikungunya virus (CHIKV) and the capsid protein of the Sindbis virus (SIN) (4,47). In the case of CHIKV, p62 binds to ubiquitinated capsid and targets it to autophagic degradation, while in the case of the SIN, and reminiscent of our data for Tat, the interaction between p62 and the SIN capsid does not require the p62 UBA domain, highlighting a potential original mechanism by which p62 recognizes autophagic substrates.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Sagnier

Daussy

Borel

et al. 2015

J Virol

127

130

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Autophagy is a ubiquitous mechanism involved in the lysosomal-mediated degradation of cellular components when they are engulfed in vacuoles called autophagosomes. Autophagy is also recognized as an important regulator of the innate and adaptive immune responses against numerous pathogens, which have, therefore, developed strategies to block or use the autophagy machinery to their own benefit. Upon human immunodeficiency virus type 1 (HIV-1) infection, viral envelope (Env) glycoproteins induce autophagy-dependent apoptosis of uninfected bystander CD4؉ T lymphocytes, a mechanism likely contributing to the loss of CD4 ؉ T cells. In contrast, in productively infected CD4 ؉ T cells, HIV-1 is able to block Env-induced autophagy in order to avoid its antiviral effect. To date, nothing is known about how autophagy restricts HIV-1 infection in CD4 ؉ T lymphocytes. Here, we report that autophagy selectively degrades the HIV-1 transactivator Tat, a protein essential for viral transcription and virion production. We demonstrated that this selective autophagy-mediated degradation of Tat relies on its ubiquitin-independent interaction with the p62/SQSTM1 adaptor. Taken together, our results provide evidence that the anti-HIV effect of autophagy is specifically due to the degradation of the viral transactivator Tat but that this process is rapidly counteracted by the virus to favor its replication and spread. IMPORTANCE Autophagy is recognized as one of the most ancient and conserved mechanisms of cellular defense against invading pathogens.Cross talk between HIV-1 and autophagy has been demonstrated depending on the virally challenged cell type, and HIV-1 has evolved strategies to block this process to replicate efficiently. However, the mechanisms by which autophagy restricts HIV-1 infection remain to be elucidated. Here, we report that the HIV-1 transactivator Tat, a protein essential for viral replication, is specifically degraded by autophagy in CD4 ؉ T lymphocytes. Both Tat present in infected cells and incoming Tat secreted from infected cells are targeted for autophagy degradation through a ubiquitin-independent interaction with the autophagy receptor p62/SQSTM1. This study is the first to demonstrate that selective autophagy can be an antiviral process by degrading a viral transactivator. In addition, the results could help in the design of new therapies against HIV-1 by specifically targeting this mechanism. M acroautophagy, herein referred to as autophagy, is a major cellular catabolic pathway highly regulated in eukaryotes. It is involved in the degradation of cytoplasmic material after its sequestration in vacuoles called autophagosomes. The autophagosomes fuse with lysosomes to form autolysosomes in which the sequestered material is degraded and then recycled (1). Since the discovery of the Atg genes that regulate this process, autophagy has been found to be involved in a number of important cellular functions, including cellular homeostasis, development, aging, or innate and adaptive immune responses (2...

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Section: Discussionmentioning

confidence: 99%

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Sagnier

Daussy

Borel

et al. 2015

J Virol

127

130

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“…In xenophagy, ubiquitination of invading bacteria is required for antimicrobial autophagy through p62 cargo recognition and degradation (36). In a similar manner to antiviral autophagy (virophagy), capsids of Sindbis virus and Chikungunya virus are targets of autophagosomes through binding of p62, and Chikungunya virus capsids are also modified by ubiquitin (37,38). Therefore, future studies should elucidate whether ISG15 enhances degradation or sequestration of viral proteins via p62-and HDAC6-mediated selective autophagy.…”

Section: Pepa/e64dmentioning

confidence: 99%

Interferon-stimulated Gene 15 (ISG15) and ISG15-linked Proteins Can Associate with Members of the Selective Autophagic Process, Histone Deacetylase 6 (HDAC6) and SQSTM1/p62

Nakashima

Nguyen

Goins

et al. 2015

Journal of Biological Chemistry

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Background: ISG15 is a Ub-like protein that conjugates cellular and pathogenic proteins during the innate immune response. Results: ISG15 associates with the selective autophagic factors HDAC6 and p62, leading to degradation of ISG15 conjugates. Conclusion:The IFN response leads to ISG15 expression allowing for its association with HDAC and p62. This may mark proteins for autophagy. Significance: This finding provides evidence of an interferon-stimulated pathway linked to autophagy.

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“…CHIKV nsP2 and nsP3 display activities that counteract some of these antiviral responses (94). Authophagy is proposed to play a global pro-CHIKV function in human cells, possibly by limiting apoptosis, and may be a pathogenesis determinant (95)(96)(97). Although some additional proviral host factors have been identified (70, 74, 78, 98-100), specific host pathways and mechanisms that promote replication of to a week and may occur in a biphasic manner (2,120).…”

Section: Disease Mechanisms and Host Immune Responsesmentioning

confidence: 99%

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

Silva¹,

Dermody²

2017

Journal of Clinical Investigation

308

338

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Species‐specific impact of the autophagy machinery on Chikungunya virus infection

Cited by 124 publications

References 35 publications

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Interferon-stimulated Gene 15 (ISG15) and ISG15-linked Proteins Can Associate with Members of the Selective Autophagic Process, Histone Deacetylase 6 (HDAC6) and SQSTM1/p62

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

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Species‐specific impact of the autophagy machinery on Chikungunya virus infection

Cited by 124 publications

References 35 publications

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 + T Lymphocytes

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 + T Lymphocytes

Interferon-stimulated Gene 15 (ISG15) and ISG15-linked Proteins Can Associate with Members of the Selective Autophagic Process, Histone Deacetylase 6 (HDAC6) and SQSTM1/p62

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

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Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes

Autophagy Restricts HIV-1 Infection by Selectively Degrading Tat in CD4 ⁺ T Lymphocytes