The molecular basis of JAK/STAT inhibition by SOCS1

Abstract

The SOCS family of proteins are negative-feedback inhibitors of signalling induced by cytokines that act via the JAK/STAT pathway. SOCS proteins can act as ubiquitin ligases by recruiting Cullin5 to ubiquitinate signalling components; however, SOCS1, the most potent member of the family, can also inhibit JAK directly. Here we determine the structural basis of both these modes of inhibition. Due to alterations within the SOCS box domain, SOCS1 has a compromised ability to recruit Cullin5; however, it is a direct, potent and selective inhibitor of JAK catalytic activity. The kinase inhibitory region of SOCS1 targets the substrate binding groove of JAK with high specificity and thereby blocks any subsequent phosphorylation. SOCS1 is a potent inhibitor of the interferon gamma (IFNγ) pathway, however, it does not bind the IFNγ receptor, making its mode-of-action distinct from SOCS3. These findings reveal the mechanism used by SOCS1 to inhibit signalling by inflammatory cytokines.

Tumor-Intrinsic Response to IFNγ Shapes the Tumor Microenvironment and Anti-PD-1 Response in NSCLC

“…Since the lack of an IFN response in LLC cells is not due to lack of receptor expression, we examined differences in expression of putative regulators of the IFN pathway between the responsive CMT167 and unresponsive LLC cell lines. We determined that at baseline, LLC cells expressed markedly higher levels of Socs1, or suppressor of cytokine signaling 1, which is a critical negative regulator of interferon signaling (Figure 3A) [27,28]. We confirmed that LLC cells expressed higher levels of both SOCS1 protein and mRNA relative to CMT167 cells in vitro (Figure 3B-C).…”

Effect of smoking on the DNA methylation pattern of the SOCS1 promoter in epithelial cells from the saliva of patients with chronic periodontitis

“…In addition, they also modulate the expression of RANKL (receptor activator of nuclear factor kappa‐Β ligand) which is responsible for bone resorption and consequent bone loss in CP . The SOCS1 protein is also a potent inhibitor of the IFN (interferon) and IL‐2 family signaling cascades . Additionally, it has also been postulated that the levels of these cytokines are increased in smokers and patients with chronic periodontal disease .…”

“…16 The SOCS1 protein is also a potent inhibitor of the IFN (interferon) and IL-2 family signaling cascades. 43 Additionally, it has also been postulated that the levels of these cytokines are increased in smokers and patients with chronic periodontal disease. 44 Moreover, polymorphisms in the IL-2 gene may be involved in the pathogenesis of periodontitis.…”

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

“…Among these, CBLB has been best studied as an intracellular immune checkpoint that can be targeted in T cells to improve tumor control in mouse models (Chiang et al, 2007;Hinterleitner et al, 2012). Targeting SOCS1, a negative regulator of JAK/STAT signaling in T cells, showed enhanced T cell clearance comparable to CBLB (Liau et al, 2018). Ablation of TCEB2, a binding partner of SOCS1, also improved tumor clearance, suggesting that the SOCS1/TCEB2 complex restrains T cell responses and is a potential target for immunotherapy (Ilangumaran et al, 2017;Kamizono et al, 2001;Liau et al, 2018).…”

“…The E3 ubiquitin-protein ligase, CBLB (rank 4) and its interacting partner, CD5 (rank 12), work together to inhibit TCR activation via ubiquitination leading to degradation of the TCR (Voisinne et al, 2016). TCEB2 (rank 5) complexes with RNF7 (rank 34), CUL5 (rank 162), and SOCS1 (rank 3), which is a key suppressor of JAK/STAT signaling in activated T cells (Kamura et al, 1998;Liau et al, 2018). UBASH3A (rank 10), TNFAIP3, and its partner TNIP1 (rank 13 and 24, respectively) inhibit TCR-induced NFkB signaling, a critical survival and growth signal for activated CD8 + T cells (Düwel et al, 2009;Ge et al, 2017).…”