TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

Abstract 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.