TRIM5α Degradation via Autophagy Is Not Required for Retroviral Restriction

Imam, Sabrina; Talley, Sarah; Nelson, Rachel S.; Dharan, Adarsh; O’Connor, Christopher; Hope, Thomas J.; Campbell, E. M.

doi:10.1128/jvi.03033-15

Cited by 40 publications

(29 citation statements)

References 44 publications

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“…As another example of a selective autophagy target, we tested whether TRIM17 could affect the autophagic targeting of TRIM5α, which has recently been reported to be protected from lysosomal degradation by autophagy inhibition (Imam et al, 2016). In agreement with these findings, mCherry-eYFP-TRIM5α showed primarily 'red' and not green fluorescence in cells, indicating its presence within acidified compartments ( Fig.…”

Section: Trim17 Inhibits Degradation Of Selective Autophagy Targetssupporting

confidence: 72%

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

Mandell

Jain

Kumar

et al. 2016

Journal of Cell Science

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TRIM proteins contribute to selective autophagy, a process whereby cells target specific cargo for autophagic degradation. In a previously reported screen, TRIM17 acted as a prominent inhibitor of bulk autophagy, unlike the majority of TRIMs, which had positive roles. Nevertheless, TRIM17 showed biochemical hallmarks of autophagyinducing TRIMs. To explain this paradox, here, we investigated how TRIM17 inhibits selective autophagic degradation of a subset of targets while promoting degradation of others. We traced the inhibitory function of TRIM17 to its actions on the anti-autophagy protein Mcl-1, which associates with and inactivates Beclin 1. TRIM17 expression stabilized Mcl-1-Beclin-1 complexes. Despite its ability to inhibit certain types of selective autophagy, TRIM17 promoted the removal of midbodies, remnants of the cell division machinery that are known autophagy targets. The selective loss of anti-autophagy Mcl-1 from TRIM17-Beclin-1 complexes at midbodies correlated with the ability of TRIM17 to promote midbody removal. This study further expands the roles of TRIMs in regulating selective autophagy by showing that a single TRIM can, depending upon a target, either positively or negatively regulate autophagy.

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Section: Trim17 Inhibits Degradation Of Selective Autophagy Targetssupporting

confidence: 72%

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

Mandell

Jain

Kumar

et al. 2016

Journal of Cell Science

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“…Notably, while the manuscript was in revision, a paper by Fletcher et al observed that TRIM5␣ assembly around restrictionsensitive viral cores triggers TRIM5␣ autoubiquitination with K63-linked ubiquitin, which drives the proteasomal degradation of TRIM5␣ (45). Our data using DUB fusions in this study are entirely consistent with such a noncanonical function of K63-linked ubiquitin and are also consistent with our previous observation that all aspects of TRIM5␣ restriction are insensitive to depletion of the key autophagic mediators Beclin1 and Atg5 (34). Such a model can also reconcile prior studies that observe that proteasomal inhibition prevents TRIM5␣-mediated core disassembly (14,17) and the degradation of TRIM5␣ observed in response to saturating levels of restriction-sensitive virus (19).…”

Section: Discussionsupporting

confidence: 91%

K63-Linked Ubiquitin Is Required for Restriction of HIV-1 Reverse Transcription and Capsid Destabilization by Rhesus TRIM5α

Imam

Kömürlü

Mattick

et al. 2019

J Virol

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TRIM5␣ is an antiviral restriction factor that inhibits retroviral infection in a species-specific fashion. TRIM5␣ binds to and forms assemblies around the retroviral capsid. Following binding, poorly understood, ubiquitin-dependent events lead to the disassembly of the viral core, prior to the accumulation of viral reverse transcription products in the target cell. It is also known that assemblies of TRIM5␣ and other TRIM family proteins can be targets of autophagic degradation. The goal of this study was to define the role of specific ubiquitin linkages in the retroviral restriction and autophagic degradation of TRIM5␣ and delineate any connection between these two processes. To this end, we generated fusion proteins in which the catalytic domains of different deubiquitinase (DUB) enzymes, with different specificities for polyubiquitinated linkages, were fused to the N-terminal RING domain of Rhesus macaque TRIM5␣. We assessed the role of ubiquitination in restriction and the degree to which specific types of ubiquitination are required for the association of TRIM5␣ with autophagic proteins. We determined that K63-linked ubiquitination by TRIM5␣ is required to induce capsid disassembly and to inhibit reverse transcription of HIV, while the ability to inhibit HIV-1 infection was not dependent on K63linked ubiquitination. We also observed that K63-linked ubiquitination is required for the association of TRIM5␣ with autophagosomal membranes and the autophagic adapter protein p62. IMPORTANCE Although the mechanisms by which TRIM5␣ can induce the abortive disassembly of retroviral capsids have remained obscure, numerous studies have suggested a role for ubiquitination and cellular degradative pathways. These studies have typically relied on global perturbation of cellular degradative pathways. Here, through the use of linkage-specific deubiquitinating enzymes tethered to TRIM5␣, we delineate the ubiquitin linkages which drive specific steps in restriction and degradation by TRIM5␣, providing evidence for a noncanonical role for K63-linked ubiquitin in the process of retroviral restriction by TRIM5␣ and potentially providing insight into the mechanism of action of other TRIM family proteins.H ost cell restriction factors are a class of proteins that inhibit viral replication by blocking specific steps of the viral life cycle. TRIM5␣ is one of the best characterized antiviral restriction factors. Members of the TRIM family of proteins are defined by having a tripartite motif consisting of an N-terminal RING domain, which functions as an E3 ubiquitin ligase, one or two B-box domains, and a coiled-coil domain (1, 2). Downloaded fromTRIM5␣ is distinguished from other members of this family by its C-terminal PRY/SPRY domain, which allows TRIM5 proteins to directly bind to the retroviral capsid, a proteinaceous core that houses the viral genome (2, 3). Upon capsid recognition, the B-box and coiled-coil domains, which are critical for self-assembly among many TRIM family members (4-7), facilitate the assembly of TRIM5 into ...

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“…In simian cells, it was observed following viral fusion that HIV Gag from incoming viral particles might be selectively targeted to autophagosomal degradation by the antiviral restriction factor TRIM5a (83). Although whether functional autophagy is required for TRIM5a-mediated HIV restriction is a matter of debate (84), these results suggest that specific adaptors might be required to target HIV Gag to autophagosomes. In the present study, we did not observe any colocalization between Gag and LC3 in productively infected DC and cells expressing Gag in the absence of other viral proteins.…”

Section: Discussionmentioning

confidence: 99%

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Coulon

Richetta

Rouers

et al. 2016

The Journal of Immunology

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It is widely assumed that CD4+ T cells recognize antigenic peptides (epitopes) derived solely from incoming, exogenous, viral particles or proteins. However, alternative sources of MHC class II (MHC-II)–restricted Ags have been described, in particular epitopes derived from newly synthesized proteins (so-called endogenous). In this study, we show that HIV-infected dendritic cells (DC) present MHC-II–restricted endogenous viral Ags to HIV-specific (HS) CD4+ T cells. This endogenous pathway functions independently of the exogenous route for HIV Ag presentation and offers a distinct possibility for the immune system to activate HS CD4+ T cells. We examined the implication of autophagy, which plays a crucial role in endogenous viral Ag presentation and thymic selection of CD4+ T cells, in HIV endogenous presentation. We show that infected DC do not use autophagy to process MHC-II–restricted HIV Ags. This is unlikely to correspond to a viral escape from autophagic degradation, as infecting DC with Nef- or Env-deficient HIV strains did not impact HS T cell activation. However, we demonstrate that, in DC, specific targeting of HIV Ags to autophagosomes using a microtubule-associated protein L chain 3 (LC3) fusion protein effectively enhances and broadens HS CD4+ T cell responses, thus favoring an endogenous MHC-II–restricted presentation. In summary, in DC, multiple endogenous presentation pathways lead to the activation of HS CD4+ T cell responses. These findings will help in designing novel strategies to activate HS CD4+ T cells that are required for CTL activation/maintenance and B cell maturation.

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TRIM5α Degradation via Autophagy Is Not Required for Retroviral Restriction

Cited by 40 publications

References 44 publications

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

K63-Linked Ubiquitin Is Required for Restriction of HIV-1 Reverse Transcription and Capsid Destabilization by Rhesus TRIM5α

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

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