Yang H, Espada CE, Phillips S, Martinez N, Kenney AD, Yount JS, Xiong Y, Wu L

Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in nondividing cells by reducing the intracellular dNTP pool. SAMHD1 also suppresses NF-?B activation induced by inflammatory stimuli and viral infections. Specifically, SAMHD1-mediated reduction of NF-?B inhibitory protein (I?B?) phosphorylation is important for the suppression of NF-?B ...

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activation. However, while the inhibitors of NF-?B kinase subunit alpha and beta (IKK? and IKK?) regulate I?B? phosphorylation, the mechanism by which SAMHD1 regulates phosphorylation of I?B? remains unclear. Here, we report that SAMHD1 suppresses phosphorylation of IKK?/?/? via interaction with IKK? and IKK?, thus inhibiting subsequent phosphorylation of I?B? in monocytic THP-1 cells and differentiated nondividing THP-1 cells. We show that knockout of SAMHD1 enhanced phosphorylation of IKK?, IKK?, and IKK? in THP-1 cells treated with the NF-?B activator lipopolysaccharide or infected with Sendai virus and SAMHD1 reconstitution inhibited phosphorylation of IKK?/?/? in Sendai virus-infected THP-1 cells. We demonstrate that endogenous SAMHD1 interacted with IKK? and IKK? in THP-1 cells and recombinant SAMHD1 bound to purified IKK? or IKK? directly in vitro. Mapping of these protein interactions showed that the HD domain of SAMHD1 interacts with both IKK? and IKK? and that the kinase domain of IKK? and the ubiquitin-like domain of IKK? are required for their interactions with SAMHD1, respectively. Moreover, we found that SAMHD1 disrupts the interaction between upstream kinase TAK1 and IKK? or IKK?. Our findings identify a new regulatory mechanism by which SAMHD1 inhibits phosphorylation of I?B? and NF-?B activation.

Date: Jun. 01, 2023

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