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Genetics
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
Two rare SNPs leading to amino acid alterations p.A946T and p.H848R are found in the IFN induced with helicase C domain 1/melanoma differentiation-associated 5 (IFIH1/MDA5) gene. These rare variants are associated with decreased risk of Ps.60 Rare variants in IFIH1 are also associated with protection from other autoimmune diseases such as type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis.61IFIH1 encodes a cytoplasmic sensor for viral double-stranded RNAs (dsRNAs) and it shares the same domain architecture as the protein encoded by the retinoic acid inducible gene-1 (RIG-1/DDX58). Although MDA5 and RIG-1 recognize distinct groups of viral RNAs, both activate the same IFN signaling pathway through the mitochondria antiviral signaling protein/interferon beta promoter stimulator protein 1 (MAVS/IPS1). Binding to dsRNA activates the IκB kinase (IKK)-related kinases, which induces the production of type I IFN through the activation of interferon regulatory factor 3 (IRF3) in addition to the activation of NF-κB transcription factors. This leads to the production of molecules such as IL-1, IL-6, TNF, type 1 IFN, and IL-9.61 The MDA5/DDX58 gene also lies in a Ps susceptibility interval. With respect to a viral response, the RIG-1-like receptor signaling pathway is also implicated through association with the protein encoded by RNF114,26 which also lies within a GWAS interval. Although the function of RNF114 is poorly understood, it is a paralog of RNF125, which encodes a Really Interesting New Gene (RING) finger domain E3 ligase (13). RNF125 suppresses dsRNA-induced IFN production by promoting the proteasomal degradation of RNA helicase RIG-I and MDA5 (16). RNF114 is a cytoplasmic protein, which can be upregulated by IFNs and dsRNA, and in a manner similar to RNF125 it associates with ubiquitinated proteins and has ubiquitin ligase activity.62
Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection
Published in Immunological Investigations, 2023
Qingzhu Shi, Ge Li, Shuaijie Dou, Lili Tang, Chunmei Hou, Zhiding Wang, Yang Gao, Zhenfang Gao, Ying Hao, Rongliang Mo, Beifen Shen, Renxi Wang, Yuxiang Li, Gencheng Han
Compared to regulation at the transcription level, the post-translational modification of RIG-I plays a more important role in immunity against virus as it provides faster control. Ubiquitination is an important post-translational modification involved in various cellular functions (Jiang and Chen 2011). E3 ubiquitin ligases have been reported to play critical roles in the regulation of RIG-I activity (Kawai and Akira 2011; Medvedev et al. 2015). The E3 ubiquitin ligase tripartite motif containing protein 25 (TRIM25), Riplet (also known as RNF135), and MEX3C deliver the K63-linked polyubiquitin moiety to RIG-I CARDs and the C-terminal domain, thus positively regulating RIG-I-mediated signaling (Gack et al. 2007; Kuniyoshi et al. 2014; Oshiumi et al. 2010). However, RING E3 ligase RNF122 and RNF125 mediate K48-linked ubiquitination of RIG-I, leading to RIG-I degradation by proteasomes, thus negatively regulating RIG-I-mediated signaling (Arimoto et al. 2007; Wang et al. 2016). Here, we found a direct interaction and co-localization between Tim-3 and RIG-I, which inspired us to investigate the mechanisms by which Tim-3 regulates RIG-I. Furthermore, we also found that Tim-3 promotes RIG-I degradation through the ubiquitin-proteasome system. RNF122, an E3 ubiquitin ligase involved in proteasome-mediated degradation of proteins, plays a critical role in the K48-linked ubiquitination of RIG-I enhanced by Tim-3. These findings demonstrate that Tim-3 interacts with RIG-I and induces proteasomal degradation of RIG-I through RNF-122.
Adipose Tissue Macrophage-Mediated Inflammation in Obesity: A Link to Posttranslational Modification
Published in Immunological Investigations, 2023
Dongqin Wei, Xin Tian, Xiangyun Zhai, Chao Sun
Under normal circumstances, the level of NLRP3 in ATMs is low. When stimulated by extracellular inflammatory mediators (such as FFA), NLRP3 is not only upregulated at the transcriptional level but also activated at the posttranscriptional level through phosphorylation and deubiquitination (Figure 5). According to numerous reports, many core components of the assembled NLRP3 inflammasome, such as nucleotide-binding and oligomerization domains (Ising et al. 2019), leucine-rich repeat domains (LRRs) (Niu et al. 2021), pyrin domain-containing protein 3 (Stutz et al. 2017), and the adaptor ASC (Hara et al. 2013), are regulated by phosphorylation. The mechanism of this phosphorylation is reviewed in detail in Song and Li (2018). Furthermore, the formation of NLRP3 inflammasomes also undergoes K63- and K48-linked polyubiquitination. Generally, in ATMs, NLRP3 is in a static state when it undergoes ubiquitination, and it is activated when it undergoes deubiquitination (Swanson et al. 2019). As an E3 ubiquitin ligase, RNF125 can initiate the K63-linked ubiquitination of LRR in NLRP3, while Cbl-b binds to LRR in NLRP3 to cause K48-linked ubiquitination to degrade the proteasome, thereby inhibiting the formation of the NLRP3 inflammasome (Tang et al. 2020). Additionally, deubiquitinase BRCA1/BRCA2-containing complex subunit 3 (BRCC3) is a key regulator of NLRP3 activity, which can activate NLRP3 inflammasome assembly through deubiquitination. This process is phosphorylated by Ser198 (or Ser194) to promote BRCC3 binding (Py et al. 2013). Upon activation, NLRP3 assembles a multimeric inflammasome complex comprising the adaptor ASC and the effector pro-caspase-1 to mediate the activation of caspase-1 (Swanson et al. 2019). The interaction between ubiquitination and phosphorylation mediates the activation of the macrophage NLRP3 inflammasome.