Caveolin‐1 frame‐shift mutation induce changes in cellular morphology and function

Abstract

Caveolins, Cav1–3, are oligomeric proteins critical for the formation of membrane caveolae that regulates cell physiology. A frameshift mutation (Cav1F160X) in Cav1 (Cav1M) was described in a patient with a progeria‐like phenotype, which presents nuclear morphology alterations. We hypothesize that Cav1M presents dominant negative function that perturb cellular physiology, particularly nuclear morphology, mitochondrial function, exocytic behavior a plasma membrane structure. Transmission electron microscopy (TEM) of patient‐derived dermal fibroblasts (PCav1M) showed abnormal nuclear shape, increased rough endoplasmic reticulum, abnormal mitochondrial size/shape, increased number of autophagosomes and reduce number of membrane caveolae. Patient‐derive serum shown an increase in exosomes and extracellular vesicles, compared with the unaffected family members. PCav1M fibroblasts showed 4‐fold increase in exosome secretion; PCav1M present also increased exosome secretion compared with Hutchinson‐Gilford progeria patient dermal fibroblasts. Nanotracking and TEM analysis revealed a significant reduction in nanoparticle size in PCav1M‐derived exosomes. Human dermal fibroblasts (HDF) treated to express Cav1M or exogenously exposed to exosomes from PCav1M fibroblasts showed altered nuclear morphology, exosome secretion profile, proteomics, and miRNA analysis. Cellular membrane structure analysis by means of membrane fractions and electron paramagnetic spectroscopy shows an altered localization of proteins commonly found in caveolae fractions and increased membrane fluidity. Our results indicate that mutations in the C‐terminus of Cav1 lead to significant membrane alterations regulating exosome secretion and other cellular morpho‐functional features. Our findings identify a novel role of caveolin in linking plasma and nuclear membrane dynamics that have potential implications for cellular communication, impacting physiology and pathophysiology.Support or Funding InformationNational Institutes of Health (HL091071, AG052722) and Veterans Administration (BX001963).