Aberrant PCM1 accumulation in Trisomy 21 mislocalizes E3 ligases, delaying primary ciliogenesis

Abstract

Primary cilia are microtubule-based extracellular signaling structures essential for development and tissue homeostasis, and their defects can cause ciliopathies. Trisomy 21, the cause of Down syndrome, also disrupts cilia formation and function. Here we show that Pericentrin (PCNT), a chromosome 21 resident gene whose protein is elevated in Trisomy 21, impairs primary ciliogenesis by delaying mother centriole uncapping. Elevated PCNT forms pericentrosomal assemblies that promote the accumulation of PCM1 in the pericentrosomal compartment. PCM1 binds and localizes the CP110 E3 ubiquitin ligases HERC2 and MIB1 to the centrosome, so mislocalizing PCM1 depletes these ligases from the centrosome, lowering CP110 ubiquitination and delaying uncapping. Reducing PCNT rescues these defects, whereas elevating PCM1 phenocopies them, establishing PCM1 accumulation as a critical mediator of uncapping. These findings reveal how a dosage-sensitive chromosome 21 gene disrupts ciliogenesis and show that centrosome function depends not only on PCM protein composition but on the spatial partitioning of proteins between the centrosome and pericentrosomal compartments.