PMID- 30988392
OWN - NLM
STAT- MEDLINE
DCOM- 20201015
LR  - 20210109
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Apr 15
TI  - Mutation-specific peripheral and ER quality control of hERG channel cell-surface 
      expression.
PG  - 6066
LID - 10.1038/s41598-019-42331-6 [doi]
LID - 6066
AB  - Impaired functional plasma membrane (PM) expression of the hERG K(+)-channel is 
      associated with Long-QT syndrome type-2 (LQT2) and increased risk of cardiac 
      arrhythmia. Reduced PM-expression is primarily attributed to retention and 
      degradation of misfolded channels by endoplasmic reticulum (ER) protein quality 
      control (QC) systems. However, as the molecular pathogenesis of LQT2 was defined 
      using severely-misfolded hERG variants with limited PM-expression, the potential 
      contribution of post-ER (peripheral) QC pathways to the disease phenotype remains 
      poorly established. Here, we investigate the cellular processing of 
      mildly-misfolded Per-Arnt-Sim (PAS)-domain mutant hERGs, which display incomplete 
      ER-retention and PM-expression defects at physiological temperature. We show that 
      the attenuated PM-expression of hERG is dictated by mutation-specific 
      contributions from both the ER and peripheral QC systems. At the ER, PAS-mutants 
      experience inefficient conformational maturation coupled with rapid 
      ubiquitin-dependent proteasomal degradation. In post-ER compartments, they are 
      rapidly endocytosed from the PM via a ubiquitin-independent mechanism and rapidly 
      targeted for lysosomal degradation. Conformational destabilization underlies 
      aberrant cellular processing at both ER- and post-ER compartments, since 
      conformational correction by a hERG-specific pharmacochaperone or 
      low-temperatures can restore WT-like trafficking. Our results demonstrate that 
      the post-ER QC alone or jointly with the ER QC determines the 
      loss-of-PM-expression phenotype of a subset of LQT2 mutations.
FAU - Foo, Brian
AU  - Foo B
AD  - Department of Physiology, McGill University, Montreal, H3G 1Y6, Quebec, Canada.
FAU - Barbier, Camille
AU  - Barbier C
AD  - Department of Physiology, McGill University, Montreal, H3G 1Y6, Quebec, Canada.
FAU - Guo, Kevin
AU  - Guo K
AD  - Department of Physiology, McGill University, Montreal, H3G 1Y6, Quebec, Canada.
AD  - Department of Biochemistry, McGill University, Montreal, H3G 1Y6, Quebec, Canada.
AD  - Institut de Recherches Cliniques de Montreal (IRCM), Montreal, H2W 1R7, Quebec, 
      Canada.
FAU - Vasantharuban, Jaminie
AU  - Vasantharuban J
AD  - Department of Physiology, McGill University, Montreal, H3G 1Y6, Quebec, Canada.
AD  - Avara Pharmaceutical Services, Boucherville, J4B 7K8, Quebec, Canada.
FAU - Lukacs, Gergely L
AU  - Lukacs GL
AD  - Department of Physiology, McGill University, Montreal, H3G 1Y6, Quebec, Canada.
AD  - Department of Biochemistry, McGill University, Montreal, H3G 1Y6, Quebec, Canada.
FAU - Shrier, Alvin
AU  - Shrier A
AD  - Department of Physiology, McGill University, Montreal, H3G 1Y6, Quebec, Canada. 
      alvin.shrier@mcgill.ca.
LA  - eng
GR  - GSD-134827/Gouvernement du Canada | Canadian Institutes of Health Research 
      (Instituts de Recherche en Santé du Canada)/International
GR  - MOP-111088/Gouvernement du Canada | Canadian Institutes of Health Research 
      (Instituts de Recherche en Santé du Canada)/International
GR  - MOP-133451/Gouvernement du Canada | Canadian Institutes of Health Research 
      (Instituts de Recherche en Santé du Canada)/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190415
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (KCNH2 protein, human)
RN  - Long Qt Syndrome 2
SB  - IM
MH  - Cell Membrane/*metabolism
MH  - Cryoelectron Microscopy
MH  - ERG1 Potassium Channel/genetics/*metabolism/ultrastructure
MH  - Endocytosis/genetics
MH  - Endoplasmic Reticulum/*metabolism
MH  - *Endoplasmic Reticulum-Associated Degradation
MH  - HeLa Cells
MH  - Humans
MH  - Long QT Syndrome/genetics/*pathology
MH  - Mutagenesis, Site-Directed
MH  - Mutation
MH  - Protein Domains/genetics
MH  - Protein Folding
MH  - Ubiquitination/genetics
PMC - PMC6465299
COIS- The authors declare no competing interests.
EDAT- 2019/04/17 06:00
MHDA- 2020/10/21 06:00
PMCR- 2019/04/15
CRDT- 2019/04/17 06:00
PHST- 2018/08/14 00:00 [received]
PHST- 2019/03/28 00:00 [accepted]
PHST- 2019/04/17 06:00 [entrez]
PHST- 2019/04/17 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2019/04/15 00:00 [pmc-release]
AID - 10.1038/s41598-019-42331-6 [pii]
AID - 42331 [pii]
AID - 10.1038/s41598-019-42331-6 [doi]
PST - epublish
SO  - Sci Rep. 2019 Apr 15;9(1):6066. doi: 10.1038/s41598-019-42331-6.