Journal Article

Interaction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability

Schaper, Fred, Williams, Jamie J. L., Baillie, George S., Palmer, Timothy M., Mullen, William, Liu, Libin, Burchmore, Richard, Pilch, Paul F., Alotaiq, Nasser

2018

Overview

Effective suppression of JAK–STAT signalling by the inducible inhibitor “suppressor of cytokine signalling 3” (SOCS3) is essential for limiting signalling from cytokine receptors. Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3-interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby reducing caveola abundance in endothelial cells. Moreover, the interaction of cavin-1 and SOCS3 is essential for SOCS3 function, as loss of cavin-1 enhances cytokine-stimulated STAT3 phosphorylation and abolishes SOCS3-dependent inhibition of IL-6 signalling by cyclic AMP. Together, these findings reveal a new functionally important mechanism linking SOCS3-mediated inhibition of cytokine signalling to localisation at the plasma membrane via interaction with and stabilisation of cavin-1. SOCS3 is an important negative feedback inhibitor of JAK–STAT-mediated cytokine signalling. Here the authors implicate cavin-1 — an essential component of caveolae — in the recruitment of SOCS3 to the plasma membrane to prevent sustained cytokine receptor signalling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 42/41 / 631/45/127/1213 / 631/80/86/2368 / 82/29 / 82/80 / 82/83 / 96/1 / 96/106 / 96/109 / 96/21 / 96/35 / 96/63 / Animals / Caveolae / Caveolae - physiology / Caveolin / Caveolin-1 / Clonal deletion / Cyclic AMP / Cytokine receptors / Cytokines / Endothelial cells / Gene Deletion / Gene Expression Regulation / HEK293 Cells / Humanities and Social Sciences / Humans / Interleukin 6 / Janus Kinases - genetics / Janus Kinases - metabolism / Localization / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / multidisciplinary / Phosphorylation / Protein Binding / Proteins / Receptors / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Signaling / SOCS-3 protein / STAT Transcription Factors - genetics / STAT Transcription Factors - metabolism / Stat3 protein / Suppressor of Cytokine Signaling 3 Protein - genetics / Suppressor of Cytokine Signaling 3 Protein - metabolism