Centriolar Protein POC5 Regulates Human Adipogenesis and Cellular Senescence: Insights From a Novel Metabolic...

Centrosomes and primary cilia regulate cellular processes, including microtubule organization and lineage-specific differentiation. POC5, a core component of the centriolar inner scaffold, has been linked to syndromic ciliopathies, yet its role in adipose biology remains unclear. This study investigates the impact of POC5 deficiency on ciliary organization, cellular senescence, adipogenesis, and insulin signaling. To this end, we analyzed primary dermal fibroblasts from a patient carrying a novel homozygous p.(Gln206Ter) POC5 variant and performed mechanistic evaluations in human adipose stem cells (ASCs) with CRISPR-Cas9-mediated POC5 knockout. Centriolar architecture was examined using Ultrastructure Expansion Microscopy (U-ExM), and cellular phenotypes were assessed through proliferation, senescence, and signaling analyses. POC5-deficient fibroblasts showed marked disruption of centriolar architecture, including absent or abnormal primary cilia and supernumerary centrioles. These defects were associated with a 35% decrease in proliferation and a premature senescence, evidenced by increased SA-β-gal activity and upregulation of p-p53, p16, and p21. Moreover, insulin signaling was impaired, with reduced phosphorylation of IRβ, AKT, and ERK1/2. These phenotypes were recapitulated in POC5-KO ASCs, which additionally exhibited a near complete block of adipogenic differentiation, associated with downregulation of PPARγ, C/EBPα, and SREBP1c. Overall, POC5 deficiency promotes insulin resistance and premature senescence, and impaired adipogenesis. These findings identify POC5-related disease as a centrosomal metabolic disorder and highlight the importance of centriolar integrity in systemic energy homeostasis, supporting the need for metabolic monitoring in individuals with POC5 pathogenic variants.