TRIM 21‐mediated proteasomal degradation of SAMHD 1 regulates its antiviral activity

• Published in: EMBO reports 2020-01, Vol.21 (1)
• Main Authors: Li, Zhaolong, Huan, Chen, Wang, Hong, Liu, Yue, Liu, Xin, Su, Xing, Yu, Jinghua, Zhao, Zhilei, Yu, Xiao‐Fang, Zheng, Baisong, Zhang, Wenyan
• Format: Article
• Language: English
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201847528

SAMHD 1 possesses multiple functions, but whether cellular factors regulate SAMHD 1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK 293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD 1 is a restriction factor for EV71. Importantly, we identify TRIM 21, an E3 ubiquitin ligase, as a key regulator of SAMHD 1, which specifically interacts and degrades SAMHD 1 through the proteasomal pathway. However, TRIM 21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM 21 and SAMHD 1 expression, whereas increasing TRIM 21 overrides SAMHD 1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM 21‐mediated degradation of SAMHD 1 also affects SAMHD 1‐dependent restriction of HIV ‐1 and the regulation of interferon production. We further identify the functional domains in TRIM 21 required for SAMHD 1 binding and the ubiquitination site K622 in SAMHD 1 and show that phosphorylation of SAMHD 1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD 1 inhibition via the upregulation of TRIM 21. image SAMHD 1, a well‐studied HIV ‐1 restriction factor, counteracts also the hand‐foot‐and‐mouth disease pathogen EV71. Upon infection, the E3 ligase TRIM 21 is up‐regulated in an IFN ‐dependent manner to induce SAMHD 1 degradation and to relieve virus restriction. Host restriction factor SAMHD 1 inhibits the replication of hand‐foot‐and‐mouth disease virus EV71. TRIM 21 specifically interacts and degrades SAMHD 1 through K48‐ubiquitination and proteasomal degradation. TRIM 21 is up‐regulated upon EV71 infection in an IFN ‐dependent manner. TRIM 21‐mediated degradation of SAMHD 1 also affects HIV ‐1 restriction and increases interferon production.