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Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response

ABSTRACT: Caveolae-associated protein 3 (cavin3), a putative tumor suppressor protein, is inactivated in most cancers. The molecular basis for its actions remains poorly understood. We characterized the effects on the proteome of cavin3 loss by utilizing genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair pathways with downregulation of BRCA1 and the BRCA1 A-complex components. Using cellular and cell-free expression assays, we show a direct interaction between BRCA1 and cavin3. Association of BRCA1 and cavin3 occurs when cavin3 is released from disassembling caveolae by multiple stressors such as UV and mechanical stress. Cavin3-deficient cells were sensitised to PARP inhibition and showed a loss of components of the BRCA1 A-complex associated with UV DNA damage foci. Overexpression and RNAi-depletion strategies in several cancer cell lines revealed that cavin3 sensitized a variety of cancer cells to UV-induced apoptosis. We conclude that cavin3 functions together with BRCA1 in multiple pathways that contribute to tumorigenesis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: David Stroud

LAB HEAD: David Stroud

PROVIDER: PXD026724 | Pride | 2021-06-15

REPOSITORIES: Pride

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			Action	DRS
	P1DAS20170605_07-HeLa_170621223735.raw	Raw
	P1DAS20170605_08-HeLa_170622044124.raw	Raw
	P1DAS20170605_09-HeLa_170622104500.raw	Raw
	P1DAS20170605_10-Cavin3_170621042625.raw	Raw
	P1DAS20170605_11-Cavin3_170621103006.raw	Raw

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Identification of Cavin3 interacting proteins

Project description:Caveolae are specialized domains of the plasma membrane. Formation of these invaginations is dependent on the expression of Caveolin-1 or -3 and proteins of the cavin family. In response to stress, caveolae disassemble and cavins are released from caveolae, allowing cavins to potentially interact with intracellular targets. Here, we describe the intracellular (non-plasma membrane) cavin interactome using biotin affinity proteomics and mass spectrometry. We validate 47 potential cavin-interactor proteins using a cell-free expression system and protein-protein binding assays. These data, together with pathway analyses, revealed novel roles for cavin proteins in metabolism and stress signaling. We validated the interaction between one candidate interactor protein, protein phosphatase 1 alpha (PP1α), and Cavin-1 and -3 and show that UV treatment causes release of Cavin3 from caveolae allowing interaction with, and inhibition of, PP1α. This interaction increases H2AX phosphorylation to stimulate apoptosis, identifying a pro-apoptotic signaling pathway from surface caveolae to the nucleus.

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Expression data from WT and Cavin-3 knockout mice adipose tissue

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