The endoplasmic reticulum (ER) membrane protein complex (EMC) is responsible for monitoring the biogenesis and synthetic quality of membrane proteins with tail-anchored or multiple transmembrane domains. The EMC subunit EMC6 is one of the core members of EMC and forms an enclosed hydrophilic vestibule in cooperation with EMC3. Despite studies demonstrating that deletion of EMC3 led to rhodopsin mislocalization in rod photoreceptors of mice

the precise mechanism leading to the failure of rhodopsin trafficking remains unclear. Here

we generated the first rod photoreceptor-specific knockout of

Emc6

(RKO) and cone photoreceptor-specific knockout of

Emc6

(CKO) mouse models. Deficiency of

Emc6

in rod photoreceptors led to progressive shortening of outer segments (OS)

impaired visual function

mislocalization and reduced expression of rhodopsin

and increased gliosis in rod photoreceptors. In addition

CKO mice displayed the progressive death of cone photoreceptors and abnormal localization of cone opsin protein. Subsequently

proteomics analysis of the RKO mouse retina illustrated that several cilium-related proteins

particularly anoctamin-2 (ANO2) and transmembrane protein 67 (TMEM67)

were significantly down-regulated prior to OS degeneration. Detrimental rod photoreceptor cilia and mislocalized membrane disc proteins were evident in RKO mice. Our data revealed that in addition to monitoring the synthesis of rhodopsin-dominated membrane disc proteins

EMC6 also impacted rod photoreceptors' ciliogenesis by regulating the synthesis of membrane proteins associated with cilia

contributing to the mislocalization of membrane disc proteins.