DDX58 is K63 polyubiquitinated

Stable Identifier
Reaction [transition]
Homo sapiens
Related Species
Influenza A virus, Rotavirus, Hepatitis C Virus, Severe acute respiratory syndrome coronavirus 2
K-63-linked polyubiquitination of RIG-I
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On viral infection antiviral innate immune response receptor RIG-I (RIG‑I, also known as probable ATP-dependent RNA helicase DDX58 or DEAD box protein 58) undergoes robust ubiquitination at its N-terminal Caspase activation and recruitment domain (CARD) region. E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25), TRIM4, members of the tripartite motif (TRIM) protein family, and E3 ubiquitin-protein ligase RNF135 (RNF135, REUL) are the E3 ligases involved in K63-linked polyubiquitination (K63polyUb) of DDX58 (Gack MU 2007; Gao D et al. 2009; Oshiumi H et al. 2009; Yan J et al. 2014). TRIM25 contains a cluster of domains including a RING-finger domain, a B box/coiled-coil domain and a SPRY domain. The interaction is mediated by the SPRY domain of TRIM25 and the N-terminal CARDs of DDX58. The polyubiquitin chains added by TRIM25 are unanchored. The lysine-172 (K172) residue of DDX58 is critical for efficient TRIM25-mediated ubiquitination and for binding of Mitochondrial Antiviral-Signaling protein (MAVS, IPS-1), as well as the ability of DDX58 to induce antiviral signal transduction (Gack MU 2007). RNF135 associates with DDX58 through its PRY and SPRY domains. The K154, K164, and K172 residues of the DDX58 CARD domain are critical for efficient RNF135-mediated ubiquitination and for the ability of DDX58 to induce antiviral signal transduction. (Gao D et al. 2009). TRIM4 also interacts with the N-terminal CARDs of DDX58 and targets DDX58 at K154, K164, and K172 for K63-linked polyubiquitination (Yan J et al. 2014).

The severe acute respiratory syndrome coronavirus type 1 (SARS-CoV-1) nucleocapsid (N) protein was found to inhibit TRIM25-mediated DDX58 ubiquitination upon coexpression in HEK293T cells in a dose-dependent manner (Hu Y et al. 2017). Similar results were reported for the SARS-CoV-2 N protein (Gori Savellini G et al. 2021).

Literature References
PubMed ID Title Journal Year
17392790 TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity

Takeuchi, O, Gack, MU, Joo, CH, Inoue, S, Akira, S, Shin, YC, Liang, C, Jung, JU, Sun, L, Urano, T, Chen, Z

Nature 2007
19017631 Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection

Matsumoto, M, Hatakeyama, S, Oshiumi, H, Seya, T

J Biol Chem 2009
24755855 TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination

Hu, MM, Mao, AP, Yan, J, Shu, HB, Li, Q

J Mol Cell Biol 2014
20403326 Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity

Chen, X, Xu, M, Hou, F, Adhikari, A, Zeng, W, Chen, ZJ, Sun, L, Jiang, X

Cell 2010
19484123 REUL is a novel E3 ubiquitin ligase and stimulator of retinoic-acid-inducible gene-I

Chen, DY, Gao, D, Yang, YK, Jiang, ZF, Diao, FC, Zhou, X, Zhai, ZH, Wang, RP, Li, MD

PLoS One 2009
Catalyst Activity

ubiquitin-protein transferase activity of RNF135,TRIM25,TRIM4 [cytosol]

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