TRIM5α SPRY/coiled-coil interactions optimize avid retroviral capsid recognition

Roganowicz, Marcin D.; Kömürlü, Sevnur; Mukherjee, Santanu; Plewka, Jacek; Alam, Steven L.; Skorupka, Katarzyna; Wan, Yuqing; Dawidowski, Damian; Cafiso, David S.; Ganser‐Pornillos, Barbie K.; Campbell, E. M.; Pornillos, Owen

doi:10.1371/journal.ppat.1006686

Cited by 22 publications

(25 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multivalent interactions between proteins that afford stronger interactions with a target when individual units have limited avidity is a key component of TRIM5α recognition. In the TRIM5α dimer, the SPRY domains have been shown to couple and form sturdier bonds with the HIV capsid [66]. This increase in avidity is achieved through the formation of α-helical folds in the long linker (L2) region that connects the RBCC and SPRY domains [66,67].…”

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

“…In the TRIM5α dimer, the SPRY domains have been shown to couple and form sturdier bonds with the HIV capsid [66]. This increase in avidity is achieved through the formation of α-helical folds in the long linker (L2) region that connects the RBCC and SPRY domains [66,67]. The presence of this α-helix allows for packing of the CC/L2/SPRY regions to create distinct arrangements of SPRY dimers that more closely match retroviral capsids [66].…”

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

“…This increase in avidity is achieved through the formation of α-helical folds in the long linker (L2) region that connects the RBCC and SPRY domains [66,67]. The presence of this α-helix allows for packing of the CC/L2/SPRY regions to create distinct arrangements of SPRY dimers that more closely match retroviral capsids [66]. This stiffer formation of the SPRY dimer was found to promote TRIM5α avidity, and mutations that interrupted this packing arrangement without disturbing the SPRY dimer (I193A, E201A) reduced the restriction efficacy [66].…”

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

“…The presence of this α-helix allows for packing of the CC/L2/SPRY regions to create distinct arrangements of SPRY dimers that more closely match retroviral capsids [66]. This stiffer formation of the SPRY dimer was found to promote TRIM5α avidity, and mutations that interrupted this packing arrangement without disturbing the SPRY dimer (I193A, E201A) reduced the restriction efficacy [66]. TRIM5α's B-box 2 domain is necessary for the formation of higher-order complexes that direct the characteristic retroviral capsid binding and restriction [68].…”

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

See 3 more Smart Citations

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

View full text Add to dashboard Cite

The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

show abstract

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

Section: Proteasome-independent Antiviral Mechanismsmentioning

confidence: 99%

See 2 more Smart Citations

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…These studies indicate that TRIM5 interactions with the autophagy machinery, mediated by its LIRs, are important for its ability to signal through TAK1. However, an important caveat to these studies is that mutations of some residues found in LIR1, notably F187A, can disrupt TRIM5 self-assembly and retroviral restriction (41). Thus, our data show an involvement of the LIRs and/or of TRIM5 higher-order structures, in driving TAK1 activation.…”

Section: Resultsmentioning

confidence: 66%

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

Saha

Chisholm

Mandell

2020

Preprint

View full text Add to dashboard Cite

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 speciesspecific restriction factor that directly inhibits the viral life cycle. Additionally, it is also a patternrecognition 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 TRIM5dependent 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 demonstrate a role for autophagy in the establishment of a TRIM5α-dependent antiviral state.

show abstract

TRIM25 Binds RNA to Modulate Cellular Anti-viral Defense

Sanchez

Sparrer

Chiang

et al. 2018

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

TRIM25 is a multi-domain, RING-type E3 ubiquitin ligase of the tripartite motif family that has important roles in multiple RNA-dependent processes. In particular, TRIM25 functions as an effector of RIG-I and ZAP, which are innate immune sensors that recognize viral RNA and induce ubiquitin-dependent anti-viral response mechanisms. TRIM25 is reported to also bind RNA, but the molecular details of this interaction or its relevance to anti-viral defense have not been elucidated. Here, we characterize the RNA-binding activity of TRIM25 and find that the protein binds both single-stranded and double-stranded RNA. Multiple regions of TRIM25 contribute to this functionality, including the C-terminal SPRY domain and a lysine-rich motif in the linker segment connecting the SPRY and coiled-coil domains. RNA binding modulates TRIM25’s ubiquitination activity in vitro, its localization in cells, and its anti-viral activity. Taken together with other studies, our results indicate that RNA binding by TRIM25 has at least three important functional consequences: by enhancing ubiquitination activity, either through allosteric effects or through clustering of multiple TRIM25 molecules; by modulating the multi-domain structure of the TRIM25 dimer, and thereby structural coupling of the SPRY and RBCC elements during the ubiquitination reaction; and by facilitating subcellular localization of the E3 ligase during virus infection.

show abstract

TRIM5α SPRY/coiled-coil interactions optimize avid retroviral capsid recognition

Cited by 22 publications

References 66 publications

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

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

TRIM25 Binds RNA to Modulate Cellular Anti-viral Defense

Contact Info

Product

Resources

About