The SOCS1 KIR and SH2 domain are both required for suppression of cytokine signaling in vivo.

Cytokine 2023 May

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Suppressor Of Cytokine Signaling (SOCS) 1 is a critical negative regulator of cytokine signaling and required to protect against an excessive inflammatory response. Genetic deletion of Socs1 results in unrestrained cytokine signaling and neonatal lethality, characterised by an inflammatory immune infiltrate in multiple organs. Overexpression and structural studies have suggested that the SOCS1 kinase inhibitory region (KIR) and Src homology 2 (SH2) domain are important for interaction with and inhibition of the receptor-associated JAK1, JAK2 and TYK2 tyrosine kinases, which initiate downstream signaling. To investigate the role of the KIR and SH2 domain in SOCS1 function, we independently mutated key conserved residues in each domain and analysed the impact on cytokine signaling, and the in vivo impact on SOCS1 function. Mutation of the SOCS1-KIR or SH2 domain had no impact on the integrity of the SOCS box complex, however, mutation within the phosphotyrosine binding pocket of the SOCS1-SH2 domain specifically disrupted SOCS1 interaction with phosphorylated JAK1. In contrast, mutation of the KIR did not affect the interaction with JAK1, but did prevent SOCS1 inhibition of JAK1 autophosphorylation. In human and mouse cell lines, both mutants impacted the ability of SOCS1 to restrain cytokine signaling, and crucially, Socs1-R105A and Socs1-F59A mice displayed a neonatal lethality and excessive inflammatory phenotype similar to Socs1-null mice. This study defines a critical and non-redundant role for both the KIR and SH2 domain in endogenous SOCS1 function. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Citation

Karen Doggett, Narelle Keating, Farhad Dehkhoda, Grace M Bidgood, Lizeth G Meza Guzman, Evelyn Leong, Andrew Kueh, Nicos A Nicola, Nadia J Kershaw, Jeffrey J Babon, Warren S Alexander, Sandra E Nicholson. The SOCS1 KIR and SH2 domain are both required for suppression of cytokine signaling in vivo. Cytokine. 2023 May;165:156167