PMID- 38067172
OWN - NLM
STAT- MEDLINE
DCOM- 20240112
LR  - 20240131
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 12
IP  - 23
DP  - 2023 Nov 30
TI  - UBE3C Facilitates the ER-Associated and Peripheral Degradation of Misfolded CFTR.
LID - 10.3390/cells12232741 [doi]
LID - 2741
AB  - The ubiquitin E3 ligase UBE3C promotes the proteasomal degradation of cytosolic 
      proteins and endoplasmic reticulum (ER) membrane proteins. UBE3C is proposed to 
      function downstream of the RNF185/MBRL ER-associated degradation (ERAD) branch, 
      contributing to the ERAD of select membrane proteins. Here, we report that UBE3C 
      facilitates the ERAD of misfolded CFTR, even in the absence of both RNF185 and 
      its functional ortholog RNF5 (RNF5/185). Unlike RNF5/185, UBE3C had a limited 
      impact on the ubiquitination of misfolded CFTR. UBE3C knockdown (KD) resulted in 
      an additional increase in the functional ∆F508-CFTR channels on the plasma 
      membrane when combined with the RNF5/185 ablation, particularly in the presence 
      of clinically used CFTR modulators. Interestingly, although UBE3C KD failed to 
      attenuate the ERAD of insig-1, it reduced the ERAD of misfolded ∆Y490-ABCB1 and 
      increased cell surface expression. UBE3C KD also stabilized the mature form of 
      ∆F508-CFTR and increased the cell surface level of T70-CFTR, a class VI CFTR 
      mutant. These results suggest that UBE3C plays a vital role in the ERAD of 
      misfolded CFTR and ABCB1, even within the RNF5/185-independent ERAD pathway, and 
      it may also be involved in maintaining the peripheral quality control of CFTR.
FAU - Kamada, Yuka
AU  - Kamada Y
AUID- ORCID: 0009-0006-6746-9112
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
FAU - Tateishi, Hazuki
AU  - Tateishi H
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
FAU - Nakayamada, Uta
AU  - Nakayamada U
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
FAU - Hinata, Daichi
AU  - Hinata D
AUID- ORCID: 0009-0001-8329-2680
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
FAU - Iwasaki, Ayuka
AU  - Iwasaki A
AUID- ORCID: 0000-0002-4661-4759
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
FAU - Zhu, Jingxin
AU  - Zhu J
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
FAU - Fukuda, Ryosuke
AU  - Fukuda R
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
FAU - Okiyoneda, Tsukasa
AU  - Okiyoneda T
AUID- ORCID: 0000-0002-5175-2224
AD  - Department of Biomedical Sciences, School of Biological and Environmental 
      Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan.
LA  - eng
GR  - 21H00294/Japan Society for the Promotion of Science/
GR  - 22H02576/Japan Society for the Promotion of Science/
GR  - Individual Special Research Subsidy with grants/Kwansei Gakuin University/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231130
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RN  - 0 (Ubiquitin)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.26 (UBE3C protein, human)
SB  - IM
MH  - *Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism
MH  - Endoplasmic Reticulum-Associated Degradation
MH  - Ubiquitin/metabolism
MH  - *Ubiquitin-Protein Ligases/metabolism
MH  - Ubiquitination
MH  - Humans
MH  - Protein Folding
PMC - PMC10706245
OTO - NOTNLM
OT  - ABCB1
OT  - CFTR
OT  - ERAD
OT  - RNF185
OT  - RNF5
OT  - UBE3C
OT  - protein quality control
OT  - ubiquitin
COIS- The authors declare no conflict of interest.
EDAT- 2023/12/09 10:46
MHDA- 2023/12/17 13:19
PMCR- 2023/11/30
CRDT- 2023/12/09 01:03
PHST- 2023/11/13 00:00 [received]
PHST- 2023/11/24 00:00 [revised]
PHST- 2023/11/28 00:00 [accepted]
PHST- 2023/12/17 13:19 [medline]
PHST- 2023/12/09 10:46 [pubmed]
PHST- 2023/12/09 01:03 [entrez]
PHST- 2023/11/30 00:00 [pmc-release]
AID - cells12232741 [pii]
AID - cells-12-02741 [pii]
AID - 10.3390/cells12232741 [doi]
PST - epublish
SO  - Cells. 2023 Nov 30;12(23):2741. doi: 10.3390/cells12232741.