Cavin-1-mediated regulation of suppressor of cytokine signalling 3 (SOCS3) function

Alotaiq, Nasser Abdullah S. (2019) Cavin-1-mediated regulation of suppressor of cytokine signalling 3 (SOCS3) function. PhD thesis, University of Glasgow.

Abstract

A distinctive feature of many cell types, such as endothelial cells (ECs), is abundant population of small plasma membrane invaginations termed caveolae. These structures represent a distinct membrane microenvironment that are involved in regulating multiple signalling pathways. Several diseases in human, such as heart failure, degenerative muscular illness, and vascular diseases, might result due to the disruption of caveolar integrity. The main caveolar structural membrane protein is cavin-1 and it has been shown to play a major role in caveolae assembly as shown by caveolae destabilisation due to cavin-1 deletion. However, the exact cellular process that regulate the functionality of cavin-1 has not been fully elucidated. One of the signalling pathways that have been found localised and distributed within caveolae is the JAK/STAT signalling, which is downregulated via the suppressor of cytokine signalling-3 (SOCS3). Studies based on proteomic screening and biochemical analysis have revealed an interaction between cavin-1 and SOCS3. As such, we hypothesised that SOCS3/cavin-1 interaction is an important controlling element in caveolae stability and/or the pro-inflammatory signalling pathway mediated by IL-6 in the endothelial cells. In support of this hypothesis, cavin-1 protein levels were significantly reduced in SOCS3−/− murine embryonic fibroblasts (MEFs) and human endothelial angiosarcoma (AS-M.5) cells compared with their WT counterparts in the absence of any changes in cavin-1 mRNA. This was associated with a reduced stability of the cavin-1 protein in SOCS3−/− AS-M.5 cells (t1/2=3 hr) versus WT AS-M.5 cells (t1/2>8 hr), significantly reduced levels of caveolin-1 and a parallel decrease in the number of caveolae detectable in SOCS3−/− MEFs and AS-M.5 cells by transmission electron microscopy. Confocal imaging experiments also revealed that cavin-1 was required for SOCS3 localisation to the plasma membrane and effective SOCS3-mediated inhibition of IL-6 signalling. Our data suggest a novel role for SOCS3 in regulating caveolae assembly while cavin-1, acting as a scaffold protein, might aid SOCS3-dependent regulation of JAK/STAT signalling. This is the first indication of a novel role for SOCS3 in caveola homeostasis and suggests that loss of caveolae represents a novel mechanism by which chronic activation of pro-inflammatory JAK/STAT signalling could be triggered in disease. Together, these data demonstrate an important interaction between cavin-1 and SOCS3 responsible for reciprocal regulation of their respective functions.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QH Natural history > QH345 Biochemistry; R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: Palmer, Dr. Tim and Van Agtmael, Dr. Tom
• Date of Award: 2019
• Depositing User: Mrs Marie Cairney
• Unique ID: glathesis:2019-8875
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 16 May 2019 09:59
• Last Modified: 21 Aug 2019 08:23
• Thesis DOI: 10.5525/gla.thesis.8875
• URI: https://theses.gla.ac.uk/id/eprint/8875

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