UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP.
Neuronal nicotinic acetylcholine receptors (nAChRs) containing the α3 subunit are known for their prominent role in normal ganglionic transmission while their involvement in the mechanisms underlying nicotine addiction and smoking-related disease has been emerging only in recent years. The amount of information available on the maturation and trafficking of α3-containing nAChRs is limited. We previously showed that UBXN2A is a p97 adaptor protein that facilitates the maturation and trafficking of α3-containing nAChRs. Further investigation of the mechanisms of UBXN2A actions revealed that the protein interacts with CHIP (carboxyl terminus of Hsc70 interacting protein), whose ubiquitin E3 ligase activity regulates the degradation of several disease-related proteins. We show that CHIP displays E3 ligase activity toward the α3 nAChR subunit and contributes to its ubiquitination and subsequent degradation. UBXN2A interferes with CHIP-mediated ubiquitination of α3 and protects the nicotinic receptor subunit from endoplasmic reticulum associated degradation (ERAD). UBXN2A also cross-talks with VCP/p97 and HSC70/HSP70 proteins in a complex where α3 is likely to be targeted by CHIP. Overall,we identify CHIP as an E3 ligase for α3 and UBXN2A as a protein that may efficiently regulate the stability of CHIP's client substrates.
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States.
Yanfen
Y
Teng
Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, Vermillion, SD 57069, United States.
Khosrow
K
Rezvani
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States; Department of Psychiatry, 415 Curie Blvd., Clinical Research Building 219, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States. Electronic address: marielde@upenn.edu.
Mariella
M
De Biasi
D000818:Animals; D004721:Endoplasmic Reticulum / Q000502:physiology; D060746:Endoplasmic Reticulum-Associated Degradation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006056:Golgi Apparatus / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
D009687:Nuclear Proteins; D011978:Receptors, Nicotinic; C094680:nuclear protein import factor p97; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
CHIP; Proteasomal degradation; UBX domain; UBXN2A; p97; α3 Nicotinic subunit