Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum-associated protein degradation.
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 (UBQLN2) has recently been linked to ALS and frontotemporal lobar degeneration. Therefore, we examined the effect of ALS-linked UBQLN2 mutation on endoplasmic reticulum-associated protein degradation (ERAD). Compared to its wild-type counterpart, mutated UBQLN2 caused greater accumulation of the ERAD substrate Hong Kong variant of α-1-antitrypsin, although ERAD was disturbed by both UBQLN2 over-expression and knockdown. Also, UBQLN2 interacted with ubiquitin regulatory X domain-containing protein 8 (UBXD8) in vitro and in vivo, and this interaction was impaired by pathogenic mutation of UBQLN2. As UBXD8 is an endoplasmic membrane protein involved in the translocation of ubiquitinated ERAD substrates, UBQLN2 likely cooperates with UBXD8 to transport defective proteins from the endoplasmic reticulum to the cytosol for degradation, and this cell-protective function is disturbed by pathogenic mutation of UBQLN2.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania, USA.
Yuxing
Y
Xia
Linda H
LH
Yan
Bo
B
Huang
Mujun
M
Liu
Xionghao
X
Liu
Cao
C
Huang
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000071183:Autophagy-Related Proteins; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D059748:Proteolysis; D048790:Renilla; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D001798:Blood Proteins; D018797:Cell Cycle Proteins; C468782:FAF2 protein, human; D008565:Membrane Proteins; C405662:UBQLN2 protein, human; D014452:Ubiquitins
FAF2; UBQLN2; UBXD8; endoplasmic reticulum-associated protein degradation; neurodegeneration