Mutation-specific peripheral and ER quality control of hERG channel cell-surface expression.

Authors:
Brian Foo
Brian Foo
Queen's University
Canada
Kevin Guo
Kevin Guo
Washington University School of Medicine
United States
Jaminie Vasantharuban
Jaminie Vasantharuban
McGill University
Gergely L Lukacs
Gergely L Lukacs
McGill University
Montréal | Canada
Alvin Shrier
Alvin Shrier
McGill University
Canada

Sci Rep 2019 Apr 15;9(1):6066. Epub 2019 Apr 15.

Department of Physiology, McGill University, Montréal, H3G 1Y6, Québec, Canada.

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.

Download full-text PDF

Source
http://www.nature.com/articles/s41598-019-42331-6
Publisher Site
http://dx.doi.org/10.1038/s41598-019-42331-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465299PMC
April 2019
4 Reads

Publication Analysis

Top Keywords

cellular processing
8
post-er compartments
8
quality control
8
er-retention pm-expression
4
attenuated pm-expression
4
pm-expression herg
4
pm-expression defects
4
temperature attenuated
4
physiological temperature
4
herg dictated
4
defects physiological
4
mutation-specific contributions
4
experience inefficient
4
inefficient conformational
4
conformational maturation
4
pas-mutants experience
4
systems pas-mutants
4
incomplete er-retention
4
contributions peripheral
4
peripheral systems
4

Similar Publications