Hum Mol Genet. 2008 Apr 15;17(8):1109-19. doi: 10.1093/hmg/ddm383. Epub 2008 Jan 4.

Polycystin-2 is regulated by endoplasmic reticulum-associated degradation.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Liang, G., Li, Q., Tang, Y., Kokame, K., Kikuchi, T., Wu, G., Chen, X. Z.,
["Membrane Protein Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7."]
Endoplasmic reticulum(ER)-associated degradation (ERAD) is an essential process for cell homeostasis and remains not well understood. During ERAD, misfolded proteins are recognized, ubiquitinated on ER and subsequently retro-translocated/dislocated from ER to the 26S proteasome in the cytosol for proteolytic elimination. Polycystin-2 (PC2), a member of the transient receptor potential superfamily of cation channels, is a Ca channel mainly located on ER and primary cilium membranes of cells. Mutations in PC2 are associated with autosomal dominant polycystic kidney disease (ADPKD). The cellular and molecular mechanisms underlying the PC2-associated pathogenesis remain unclear. Here we show that PC2 degradation is regulated by the ERAD pathway through the ubiquitin-proteasome system. PC2 interacted with ATPase p97, a well-known ERAD component extracting substrates from ER, and immobilized it in perinuclear regions. PC2 also interacted with Herp, an ubiquitin-like protein implicated in regulation of ERAD. We found that Herp is required for and promotes PC2 degradation. ER stress accelerates the retro-translocation of PC2 for cytosolic degradation, at least in part through increasing the Herp expression. Thus, PC2 is a novel ERAD substrate. Herp also promoted, to varied degrees, the degradation of PC2 truncation mutants, including two pathogenic mutants R872X and E837X, as long as they interact with Herp. In contrast, Herp did not interact with, and has no effect on the degradation of, PC2 mutant missing both the N- and C-termini. The ERAD machinery may thus be important for ADPKD pathogenesis because the regulation of PC2 expression by the ERAD pathway is altered by mutations in PC2.
PMID: 18178578External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Screening Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Experimental screening Non-experimental screening Reference
TRP channel construct Interactor source
TRP channel Interactor Method Species Region Species Organ/tissue Sample type
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 HERP Inference Prediction 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 p97/VCP Inference Prediction 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PSMD7 Inference Prediction 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 UBC Inference Prediction 18178578
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 HERP Co-immunoprecipitation HeLa Human Full-length Mouse Full-length 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 p97/VCP Co-immunoprecipitation Mouse Inner medullary collecting duct cell 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 p97/VCP Co-immunofluorescence staining MDCK Human Full-length Not used 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PSMD7 Co-immunoprecipitation Mouse Inner medullary collecting duct cell 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 UBC Co-immunoprecipitation Mouse Inner medullary collecting duct cell 18178578
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Characterization Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Binding region mapping Stoichiometry Affinity (Kd) Reference
TRP channel Interactor
TRP channel Interactor Method Species Region Species Region
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 HERP Co-immunoprecipitation Human 1-208 Mouse Not determined 18178578
TRPP1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 HERP Co-immunoprecipitation Human 689-968 Mouse Not determined 18178578
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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