Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation

Lenoir, Jessica J.; Parisien, Jean-Patrick; Horvath, Curt M.

doi:10.1016/j.celrep.2021.110175

Cited by 19 publications

(19 citation statements)

References 56 publications

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“…We think that future studies need to further investigate in vitro and in vivo mechanisms underlying function switch of zebrafish LGP2 using knockout technologies. Recent studies have revealed that human LGP2 enhances apoptosis as an antiviral defense mechanism ( Takahashi et al., 2020 ), and LGP2 downregulates innate immune signaling by inhibiting TRAF ubiquitin ligase ( Parisien et al., 2018 ), blocking the interaction between RIG-I and MAVS ( Esser-Nobis et al., 2020 ), and the K63 conjugating enzyme Ubc13 ( Lenoir et al., 2021 ). However, our results showed that zebrafish LGP2 negatively regulates IFN response likely through attenuating tbk1 and ikki mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

LGP2 is essential for zebrafish survival through dual regulation of IFN antiviral response

et al. 2022

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Section: Discussionmentioning

confidence: 99%

LGP2 is essential for zebrafish survival through dual regulation of IFN antiviral response

et al. 2022

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“…Intrigulingly, it is also important to note that the HEL2i domain is uniquely associated with specialized RNA-activated ATPases (DRAs) that include RNA sensors, RIG-I-like receptors, the ribonuclease Dicer, and DRH-1 and DRH-3 involved in the siRNA pathway of Caenorhabditis elegans ( 9 , 10 , 52 ). Besides its role involved in RNA backbone scanning and binding, the HEL2i domain of Dicer and LGP2 plays a regulatory role in interacting with other cytosolic proteins and their signaling pathways ( 10 , 53 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

A loosened gating mechanism of RIG-I leads to autoimmune disorders

Luo

Zheng

2022

Nucleic Acids Research

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DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased susceptibility to Singleton-Merten syndrome (SMS) defects, resulting in tissue-specific (mild) and classic (severe) phenotypes. The coupling between RNA recognition and conformational changes is central to RIG-I RNA proofreading, but the molecular determinants leading to dissociated disease phenotypes remain unknown. Herein, we employed hydrogen/deuterium exchange mass spectrometry (HDX-MS) and single molecule magnetic tweezers (MT) to precisely examine how subtle conformational changes in the helicase insertion domain (HEL2i) promote impaired ATPase and erroneous RNA proofreading activities. We showed that the mutations cause a loosened latch-gate engagement in apo RIG-I, which in turn gradually dampens its self RNA (Cap2 moiety:m7G cap and N1-2-2′-O-methylation RNA) proofreading ability, leading to increased immunopathy. These results reveal HEL2i as a unique checkpoint directing two specialized functions, i.e. stabilizing the CARD2-HEL2i interface and gating the helicase from incoming self RNAs; thus, these findings add new insights into the role of HEL2i in the control of antiviral innate immunity and autoimmunity diseases.

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“…Mechanically, LGP2 disrupts K63-linked ubiquitin chains from transforming into TRIM25 by interacting with Ubc13/UBE2N, which is a K63-Ub-conjugating enzyme from the E2 family. This interaction is also present in two other K63-linked E3s (TRAF6 and RNF125) to negatively regulate innate immune signaling [ 24 , 25 ]. However, accumulating evidence has shown that LGP2 can positively regulate MDA5-mediated antiviral signaling by synergistically sensing viral dsRNA [ 26 , 27 ].…”

Section: Manipulation Of Ring-type E3s In the Rlr And Cgas-sting Path...mentioning

confidence: 99%

E3 Ubiquitin Ligases: The Operators of the Ubiquitin Code That Regulates the RLR and cGAS-STING Pathways

Wang

Zhou

et al. 2022

IJMS

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The outbreaks caused by RNA and DNA viruses, such as SARS-CoV-2 and monkeypox, pose serious threats to human health. The RLR and cGAS-STING pathways contain major cytoplasmic sensors and signaling transduction axes for host innate antiviral immunity. In physiological and virus-induced pathological states, the activation and inactivation of these signal axes are tightly controlled, especially post-translational modifications (PTMs). E3 ubiquitin ligases (E3s) are the direct manipulator of ubiquitin codons and determine the type and modification type of substrate proteins. Therefore, members of the E3s family are involved in balancing the host’s innate antiviral immune responses, and their functions have been extensively studied over recent decades. In this study, we overviewed the mechanisms of different members of three E3s families that mediate the RLR and cGAS-STING axes and analyzed them as potential molecular targets for the prevention and treatment of virus-related diseases.

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Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation

Abstract: Highlights d Immune sensor LGP2 is able to inhibit a wide variety of K63 ubiquitin ligases d The target of LGP2 inhibition is the K63 conjugating enzyme, Ubc13/UBE2N d The helicase 2i domain of LGP2 mediates the interaction with Ubc13/UBE2N

Cited by 19 publications

References 56 publications

LGP2 is essential for zebrafish survival through dual regulation of IFN antiviral response

LGP2 is essential for zebrafish survival through dual regulation of IFN antiviral response

A loosened gating mechanism of RIG-I leads to autoimmune disorders

E3 Ubiquitin Ligases: The Operators of the Ubiquitin Code That Regulates the RLR and cGAS-STING Pathways

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