title: Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform.
abstract: RIG-I is a key cytosolic RNA sensor that mediates innate immune defense against RNA virus. Aberrant RIG-I activity leads to severe pathological states such as autosomal dominant multi-system disorder, inflammatory myophathies and dermatomyositis. Therefore, identification of regulators that ensure efficient defense without harmful immune-pathology is particularly critical to deal with RIG-I-associated diseases. Here, we presented the inflammatory inducible FAT10 as a novel negative regulator of RIG-I-mediated inflammatory response. In various cell lines, FAT10 protein is undetectable unless it is induced by pro-inflammatory cytokines. FAT10 non-covalently associated with the 2CARD domain of RIG-I, and inhibited viral RNA-induced IRF3 and NF-kB activation through modulating the RIG-I protein solubility. We further demonstrated that FAT10 was recruited to RIG-I-TRIM25 to form an inhibitory complex where FAT10 was stabilized by E3 ligase TRIM25. As the result, FAT10 inhibited the antiviral stress granules formation contains RIG-I and sequestered the active RIG-I away from the mitochondria. Our study presented a novel mechanism to dampen RIG-I activity. Highly accumulated FAT10 is observed in various cancers with pro-inflammatory environment, therefore, our finding which uncovered the suppressive effect of the accumulated FAT10 during virus-mediated inflammatory response may also provide molecular clue to understand the carcinogenesis related with infection and inflammation.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea Hyoja-dong 31, Pohang, 790-784, Republic of Korea.
authors.forename: Nhung T H
authors.initials: NT
authors.lastname: Nguyen
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea Hyoja-dong 31, Pohang, 790-784, Republic of Korea.
authors.forename: Hesung
authors.initials: H
authors.lastname: Now
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea Hyoja-dong 31, Pohang, 790-784, Republic of Korea.
authors.forename: Woo-Jong
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea Hyoja-dong 31, Pohang, 790-784, Republic of Korea.
authors.forename: Nari
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea Hyoja-dong 31, Pohang, 790-784, Republic of Korea.
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
mesh_terms: D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000821:virology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D011971:Receptors, Immunologic; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C109184:UBD protein, human; D014452:Ubiquitins; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58