Abstract
Cavin-1/polymerase I and transcript release factor (PTRF) is a requisite component of caveolae, small plasma membrane invaginations that are highly abundant in adipocytes. Cavin-1 is a dynamic molecule whose dissociation from caveolae plays an important role in mechanoprotection and rRNA synthesis. In the former situation, the acute dissociation of cavin-1 from caveolae allows cell membrane expansion that occurs upon insulin-aided lipid uptake into the fat cells. Cavin-1 dissociation from caveolae and membrane flattening alters the cytoskeleton and the interaction of plasma membrane proteins with the extracellular matrix through interactions with focal adhesion structures. Here, using cavin-1 knockout mice, subcellular fractionation, and immunoblotting methods, we addressed the relationship of cavin-1 with focal adhesion complexes following nutritional stimulation. We found that cavin-1 is acutely translocated to focal complex compartments upon insulin stimulation, where it regulates focal complex formation through an interaction with paxillin. We found that loss of cavin-1 impairs focal complex remodeling and focal adhesion formation and causes a mechanical stress response, concomitant with activation of proinflammatory and senescence/apoptosis pathways. We conclude that cavin-1 plays key roles in dynamic remodeling of focal complexes upon metabolic stimulation. This mechanism also underlies the crucial role of caveolae in the long-term healthy expansion of the adipocyte.
Highlights
Cavin-1/polymerase I and transcript release factor (PTRF) is a requisite component of caveolae, small plasma membrane invaginations that are highly abundant in adipocytes
Our studies show in adipocytes that insulin stimulates cavin-1 tyrosine phosphorylation and its translocation from lipid rafts to a focal adhesion complex fraction, where it participates in focal complex formation
Cavin-1 partially localizes with focal adhesion complex by interacting with paxillin, but not focal adhesion kinase (FAK) or vinculin
Summary
We found that loss of cavin-1 impairs focal complex remodeling and focal adhesion formation and causes a mechanical stress response, concomitant with activation of proinflammatory and senescence/apoptosis pathways. We conclude that cavin-1 plays key roles in dynamic remodeling of focal complexes upon metabolic stimulation This mechanism underlies the crucial role of caveolae in the long-term healthy expansion of the adipocyte. After a 5-day high-fat diet feeding regimen, compared with WT littermates, cavin-1 null mice showed no increase in adipose tissue weight but showed hyper-FAK phosphorylation, ERK phosphorylation, and pro-inflammatory and apoptotic pathway activation These data support cavin-1 serving as a responder to insulin stimulation and “priming” a pregrowth state by caveolae-focal adhesion and. Loss of this cavin-1– dependent remodeling caused a cell size–induced stress response activation through a FAK signaling pathway and, subsequently, the activation of deleterious pro-inflammatory and cell senescence/apoptotic pathways
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