LRRC25 inhibits type I IFN signaling by targeting ISG15‐associated RIG‐I for autophagic degradation

Du, Yang; Duan, Tianhao; Feng, Yang; Liu, Qingxiang; Lin, Meng; Cui, Jun; Wang, Rong Fu

doi:10.15252/embj.201796781

Cited by 140 publications

(107 citation statements)

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“…The transmembrane protein LRRC25 is found in monocytes, dendritic cells, granulocytes and T lymphocytes. It acts as a negative regulator of the signaling pathways of NF-kB [56] and interferon [57], i.e., it suppresses the production of inflammatory cytokines and modulates the response to viral infections. The latter is a long overlooked effect of vitamin D on the immune system [58,59] and a reason why vitamin D deficiency may lead to high vulnerability against viral infections in the elderly, but also in school children [15,60,61].…”

Section: Discussionmentioning

confidence: 99%

Key Vitamin D Target Genes with Functions in the Immune System

2020

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The biologically active form of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), modulates innate and adaptive immunity via genes regulated by the transcription factor vitamin D receptor (VDR). In order to identify the key vitamin D target genes involved in these processes, transcriptome-wide datasets were compared, which were obtained from a human monocytic cell line (THP-1) and peripheral blood mononuclear cells (PBMCs) treated in vitro by 1,25(OH) 2 D 3 , filtered using different approaches, as well as from PBMCs of individuals supplemented with a vitamin D 3 bolus. The led to the genes ACVRL1, CAMP, CD14, CD93, CEBPB, FN1, MAPK13, NINJ1, LILRB4, LRRC25, SEMA6B, SRGN, THBD, THEMIS2 and TREM1. Public epigenome-and transcriptome-wide data from THP-1 cells were used to characterize these genes based on the level of their VDR-driven enhancers as well as the level of the dynamics of their mRNA production. Both types of datasets allowed the categorization of the vitamin D target genes into three groups according to their role in (i) acute response to infection, (ii) infection in general and (iii) autoimmunity. In conclusion, 15 genes were identified as major mediators of the action of vitamin D in innate and adaptive immunity and their individual functions are explained based on different gene regulatory scenarios.

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Section: Discussionmentioning

confidence: 99%

Key Vitamin D Target Genes with Functions in the Immune System

2020

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“…In most cases, an absence of autophagy promotes the RLR-mediated cytokine responses, indicating that autophagy has a dampening effect on RLR signalling. The LRRcontaining protein leucine rich repeat-containing 25 (LRRC25) recognizes RIG-I 'earmarked' with ISG15, inducing its degradation by p62-mediated selective autophagy 162 . The autophagy-related protein conjugate, ATG5-ATG12, suppresses IFN gene expression through direct binding to both RIG-I and MAVS, preventing their CARD-CARD interaction 163 .…”

Section: Regulation By Autophagymentioning

confidence: 99%

RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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| Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review , we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally , we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

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“…ISG15 negatively regulates type I IFN signaling at multiple levels. For example, ISGylation of RIG-I results in reduced levels of IFN promoter activity, and ISG15 binding targets RIG-I for autophagic degradation [25,26]. USP18 regulates antiviral responses by removing ISG15 conjugates and can directly inhibit type I IFN receptor signaling by binding the subunit 2 of the receptor via STAT-2 [27,28].…”

Section: The Intracellular Role Of Isg15mentioning

confidence: 99%

ISG15: It's Complicated

Dzimianski

Scholte

Bergeron

et al. 2019

Journal of Molecular Biology

126

114

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Interferon-stimulated gene product 15 (ISG15) is a key component of host responses to microbial infection. Despite having been known for four decades, grasping the functions and features of ISG15 has been a slow and elusive process. Substantial work over the past two decades has greatly enhanced this understanding, revealing the complex and variable nature of this protein. This has unveiled multiple mechanisms of action that are only now beginning to be understood. In addition, it has uncovered diversity not only between how ISG15 affects different pathogens but also between the function and structure of ISG15 itself between different host species. Here we review the complexity of ISG15 within the context of viral infection, focusing primarily on its antiviral function and the mechanisms viruses employ to thwart its effects. We highlight what is known regarding the impact of ISG15 sequence and structural diversity on these interactions and discuss the aspects presenting the next frontier toward elucidating a more complete picture of ISG15 function.

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LRRC25 inhibits type I IFN signaling by targeting ISG15‐associated RIG‐I for autophagic degradation

Cited by 140 publications

References 50 publications

Key Vitamin D Target Genes with Functions in the Immune System

Key Vitamin D Target Genes with Functions in the Immune System

RIG-I-like receptors: their regulation and roles in RNA sensing

ISG15: It's Complicated

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