Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum‐associated protein degradation

Abstract Protein aggregation is a common feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis ( ALS ) and frontotemporal lobar degeneration. How protein aggregates are formed and contribute to neurodegeneration, however, is not clear. Mutation of Ubiquilin 2 ( UBQLN 2) has recently been linked to ALS and frontotemporal lobar degeneration. Therefore, we examined the effect of ALS ‐linked UBQLN 2 mutation on endoplasmic reticulum‐associated protein degradation ( ERAD ). Compared to its wild‐type counterpart, mutated UBQLN 2 caused greater accumulation of the ERAD substrate Hong Kong variant of α‐1‐antitrypsin, although ERAD was disturbed by both UBQLN 2 over‐expression and knockdown. Also, UBQLN 2 interacted with ubiquitin regulatory X domain‐containing protein 8 ( UBXD 8) in vitro and in vivo, and this interaction was impaired by pathogenic mutation of UBQLN 2. As UBXD 8 is an endoplasmic membrane protein involved in the translocation of ubiquitinated ERAD substrates, UBQLN 2 likely cooperates with UBXD 8 to transport defective proteins from the endoplasmic reticulum to the cytosol for degradation, and this cell‐protective function is disturbed by pathogenic mutation of UBQLN 2. image Endoplasmic reticulum‐associated protein degradation (ERAD) is important machinery for cells to maintain protein homeostasis. We found that ERAD is disturbed by pathogenic Ubiquilin 2 mutation that is recently linked to amyotrophic lateral sclerosis (ALS). Impaired ERAD is likely involved in Ubiquilin 2 pathogenesis.