Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity

Cadena, Cristhian; Ahmad, Sadeem; Xavier, Audrey; Willemsen, Joschka; Park, Sehoon; Park, Ji Woo; Oh, Seong-Wook; Fujita, Takashi; Hou, Fanfan; Binder, Marco; Hur, Sun

doi:10.1016/j.cell.2019.03.017

Cited by 163 publications

(189 citation statements)

References 61 publications

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“…In particular, recent work by Cadena et al showed that deletion of TRIM25 from HEK293T and MEF cells results in an increase, not a reduction in RIG‐I activation in response to 5′ppp‐RNA. In contrast, deletion of Riplet from the same cell line results in complete abolition of RIG‐I signaling, to the same level as deletion of RIG‐I itself (Cadena et al, ). The same was found to be true for expression of IFNβ mRNA in response to infection with Sendai virus, with deletion of TRIM25 in this case resulting in a significant increase in IFNβ expression (Cadena et al, ).…”

Section: Trim25's Role In Innate Immunitymentioning

confidence: 98%

“…This is followed by ubiquitination at various sites on the 2CARD by Riplet, TRIM25, TRIM4 and MEX3C. This would fit with several recent observations (Cadena et al, ; Hayman et al, ; Shi et al, ) that Riplet is absolutely required for efficient RIG‐I signaling activation, while TRIM25 is not, as well as explaining why there is seemingly redundancy between the other E3 ligases. In particular, recent work by Cadena et al showed that deletion of TRIM25 from HEK293T and MEF cells results in an increase, not a reduction in RIG‐I activation in response to 5′ppp‐RNA.…”

Section: Trim25's Role In Innate Immunitymentioning

confidence: 99%

“…Here we will focus on the Tri‐partite Motif (TRIM) containing protein 25 (TRIM25), which was thought to be involved in the RIG‐I/INF pathway. Recent findings showed that TRIM25 is an RNA‐binding protein (RBP; Castello et al, ; Choudhury et al, ) and put into question its major role in the RIG‐I activation (Cadena et al, ; Hayman et al, ). We will elaborate on what is known about TRIM25 and its RNA‐binding activity and speculate how it can affect its antiviral properties.…”

Section: Introductionmentioning

confidence: 99%

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TRIM25 and its emerging RNA‐binding roles in antiviral defense

2020

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The innate immune system is the body's first line of defense against viruses, with pattern recognition receptors (PRRs) recognizing molecules unique to viruses and triggering the expression of interferons and other anti-viral cytokines, leading to the formation of an anti-viral state. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of signaling by the PRR retinoic acid-inducible gene I protein (RIG-I). TRIM25 has recently been identified as an RNA-binding protein, raising the question of whether its RNA-binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in noninfected and infected cells. We also introduce models that explain how

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Section: Trim25's Role In Innate Immunitymentioning

confidence: 98%

Section: Trim25's Role In Innate Immunitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRIM25 and its emerging RNA‐binding roles in antiviral defense

2020

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“…Much of viral sensing and immune response mechanisms derive from functional and structural studies of RIG-I (Yoneyama and Fujita, 2008). Upon binding to dsRNA, RIG-I transforms from an auto-repressed to an open conformation (Kowalinski et al, 2011); this facilitates its tetramerisation and K63-linked ubiquitylation by either TRIM25 or RIPLET (Cadena et al, 2019;Gack et al, 2007). RIG-I tetramers translocate to mitochondrial membranes (Liu et al, 2012) where they interact with mitochondrial antiviral signaling (MAVS) protein via their respective CARD domains.…”

mentioning

confidence: 99%

“…Until recently K63 ubiquitylation was thought to be catalysed interchangeably by TRIM25 and RIPLET; however, recent studies have indicated that RIG-I activation is fundamentally dependent on RIPLET (Cadena et al, 2019).…”

mentioning

confidence: 99%

OTUB1 is a key regulator of RIG-I dependent immune signalling and is targeted for proteasomal degradation by influenza A NS1

Jahan

Biquand

Muñoz-Moreno

et al. 2019

Preprint

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Running title: OTUB1 activates RIG-I during influenza virus infections Highlights 1. OTUB1 is induced during influenza A virus infections in an IFN-I dependent manner 2. OTUB1 regulates the RIG-I complex by hydrolysing K48-linked polyubiquitin chains and by sequestering UBCH5c to prevent K48 polyubiquitylation 3. Optimal K63 versus K48 polyubiquitin chain concentrations determine RIG-I activation 4. Influenza NS1 targets OTUB1 for proteasomal degradation Summary Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host innate immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, DUBs that regulate this pathway have not been identified. Using a ubiquitin C-terminal electrophile, we profiled DUBs that function during influenza A virus (IAV) infection, and isolated OTUB1 as a key regulator of RIG-I dependent antiviral responses. OTUB1 was interferon-inducible, and interacted with RIG-I, viral PB2 and NS1. Upon infection, OTUB1 relocalised from the nucleus to mitochondrial membranes, and activated the RIG-I signaling complex via hydrolysis of K48 polyubiquitin chains and by forming a repressive complex with UBCH5c. Using a reconstituted system composed of in vitro translated [ 35 S]IRF3, purified RIG-I, mitochondrial membranes and cytosol expressing OTUB1 variants, we recapitulated the mechanism of OTUB1dependent RIG-I activation. A wide range of IAV NS1 proteins triggered proteasomal degradation of OTUB1, thereby antagonizing the RIG-I signaling cascade and antiviral responses.

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Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

et al. 2021

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The ubiquitylation machinery regulates several fundamental biological processes from protein homeostasis to a wide variety of cellular signaling pathways. As a consequence, its dysregulation is linked to diseases including cancer, neurodegeneration, and autoimmunity. With this review, we aim to highlight the therapeutic potential of targeting E3 ligases, with a special focus on an emerging class of RING ligases, named tri‐partite motif (TRIM) proteins, whose role as targets for drug development is currently gaining pharmaceutical attention. TRIM proteins exert their catalytic activity as scaffolds involved in many protein–protein interactions, whose multidomains and adapter‐like nature make their druggability very challenging. Herein, we give an overview of the current understanding of this class of single polypeptide RING E3 ligases and discuss potential targeting options.

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Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity

Cited by 163 publications

References 61 publications

TRIM25 and its emerging RNA‐binding roles in antiviral defense

TRIM25 and its emerging RNA‐binding roles in antiviral defense

OTUB1 is a key regulator of RIG-I dependent immune signalling and is targeted for proteasomal degradation by influenza A NS1

Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

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