BBSome-Mediated Clearance of Ubiquitinated IMPG2 Defines a Constitutive Ciliary Retrieval Pathway in Photoreceptors

The BBSome mediates the retrieval of ubiquitinated membrane proteins from cilia, but its physiological cargoes in photoreceptors remain largely unidentified. Here, we find that K63-linked ubiquitin (UbK63) chains accumulate in the outer segment (OS, equivalent of cilia) of Bbs4 ^−/− photoreceptors from the onset of OS formation. Through quantitative profiling of the UbK63-associated OS proteome, we identify the transmembrane fragment of interphotoreceptor matrix proteoglycan 2 (IMPG2 ^m ) as a principal cargo of the BBSome. In Bbs4 ^−/− mice, ubiquitinated IMPG2 ^m aberrantly accumulates in OSs, and disruption of IMPG2 ^m ubiquitination impairs its retrieval and clearance. Because full-length IMPG2 traffics to the OS to deliver its extracellular domain to the matrix, our data support a model in which IMPG2 ^m undergoes constitutive cycling between the inner and outer segments. These findings redefine the BBSome’s role in photoreceptors from quality control to constitutive membrane protein turnover.