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The host anti-viral protein SAMHD1 suppresses NF-κB activation by interacting with the IKK complex during inflammatory responses and viral infection
Journal article   Open access   Peer reviewed

The host anti-viral protein SAMHD1 suppresses NF-κB activation by interacting with the IKK complex during inflammatory responses and viral infection

Hua Yang, Constanza E Espada, Stacia Phillips, Nicholas Martinez, Adam D Kenney, Jacob S Yount, Yong Xiong and Li Wu
The Journal of biological chemistry, Vol.299(6), 104750
06/2023
DOI: 10.1016/j.jbc.2023.104750
PMCID: PMC10318468
PMID: 37100289
url
https://doi.org/10.1016/j.jbc.2023.104750View
Published (Version of record) Open Access

Abstract

Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 also suppresses NF-κB activation induced by inflammatory stimuli and viral infections. Specifically, SAMHD1-mediated reduction of NF-κB inhibitory protein (IκBα) phosphorylation is important for the suppression of NF-κB activation. However, while the inhibitors of NF-κB kinase subunit alpha and beta (IKKα and IKKβ) regulate IκBα phosphorylation, the mechanism by which SAMHD1 regulates phosphorylation of IκBα remains unclear. Here, we report that SAMHD1 suppresses phosphorylation of IKKα/β/γ via interaction with IKKα and IKKβ, thus inhibiting subsequent phosphorylation of IκBα in monocytic THP-1 cells and differentiated non-dividing THP-1 cells. We show that knockout of SAMHD1 enhanced phosphorylation of IKKα, IKKβ, and IKKγ in THP-1 cells treated with the NF-κB activator lipopolysaccharide (LPS) or infected with Sendai virus (SeV), and SAMHD1 reconstitution inhibited phosphorylation of IKKα/β/γ in SeV-infected THP-1 cells. We demonstrate that endogenous SAMHD1 interacted with IKKα and IKKβ in THP-1 cells and recombinant SAMHD1 bound to purified IKKα or IKKβ directly in vitro. Mapping of these protein interactions showed that the HD domain of SAMHD1 interacts with both IKKα and IKKβ and that the kinase domain of IKKα and the ubiquitin-like domain of IKKβ are required for their interactions with SAMHD1, respectively. Moreover, we found that SAMHD1 disrupts the interaction between upstream kinase TAK1 and IKKα or IKKβ. Our findings identify a new regulatory mechanism by which SAMHD1 inhibits phosphorylation of IκBα and NF-κB activation.
 Immunoprecipitation Phosphorylation NF-κB viral infection TAK1 IKKγ THP-1 cells IKKα IKKβ SAMHD1

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