BBSome-Mediated Clearance of Ubiquitinated IMPG2 Defines a Constitutive Ciliary Retrieval Pathway in Photoreceptors
Das, T.; Bradshaw, G. A.; Hyer, J.; Masek, M.; Kuo, Y.-M.; Bachmann-Gagescu, R.; Kalocsay, M.; Nachury, M. V.
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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 (IMPG2m) as a principal cargo of the BBSome. In Bbs4-/- mice, ubiquitinated IMPG2m aberrantly accumulates in OSs, and disruption of IMPG2m 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 IMPG2m undergoes constitutive cycling between the inner and outer segments. These findings redefine the BBSomes role in photoreceptors from quality control to constitutive membrane protein turnover.
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