TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

Abstract

SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21-mediated degradation of SAMHD1 also affects SAMHD1-dependent restriction of HIV-1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.

Hexosamine biosynthetic pathway promotes the antiviral activity of SAMHD1 by enhancing O-GlcNAc transferase-mediated protein O-GlcNAcylation

“…HCMV infection promotes degradation of SAMHD1 at late stages through the Cullin-RING-E3 ligase complexes 56 . Enterovirus 71 infection increases TRIM21 (an E3 ubiquitin ligase) expression, and TRIM21 directly interacts and degrades SAMHD1 through the proteasomal pathway 25 . On the contrary, HBV-encoded proteins such as hepatitis B virus-X (HBx) benefits virus replication by directly or indirectly degrading multiple cellular restriction factors.…”

“…The dNTPase activity requires homo-tetramerization of the SAMHD1 protein 23 . Several post-translational modifications, including phosphorylation 24 and ubiquitination 25 , have been reported to be critical for SAMHD1 function. Our group has previously demonstrated that cyclin E2-CDK2 mediates SAMHD1 phosphorylation to abrogate its restriction of HBV replication 26 .…”

O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity

“…SAMHD1, an effector of innate immunity, can restrict most retroviruses (such as HIV-1) and several DNA viruses (including HBV) by depleting the intracellular pool of dNTPs (Ballana & Esté, 2015). Several post-translational modifications, including phosphorylation (White et al , 2013, 1) and ubiquitination (Li et al , 2019b) have been reported to be critical for SAMHD1 function. Herein, we identified Ser93 as a key O-GlcNAcylation site on SAMHD1 using LC-MS/MS.…”

SAMHD1 Functions and Human Diseases

“…This is because the dNTPase function of SAMHD1 is regulated in several ways as mentioned above. In dividing cells, SAMHD1 has been identified to directly interact with the cyclin A2/CDK complex [12,13,16,70,71], CtIP [55,72], SKP2 [13,14], PP2A-B55α [10], cyclin L2 [73], TRIM21 [74], and various proteins involved in nuclear import [48,54]. Direct binding partners of SAMHD1 in non-cycling cells are still unknown.…”