ESCRT regulates surface expression of the Kir2.1 potassium channel.
Protein quality control (PQC) is required to ensure cellular health. PQC is recognized for targeting the destruction of defective polypeptides, whereas regulated protein degradation mechanisms modulate the concentration of specific proteins in concert with physiological demands. For example, ion channel levels are physiologically regulated within tight limits, but a system-wide approach to define which degradative systems are involved is lacking. We focus on the Kir2.1 potassium channel because altered Kir2.1 levels lead to human disease and Kir2.1 restores growth on low-potassium medium in yeast mutated for endogenous potassium channels. Using this system, first we find that Kir2.1 is targeted for endoplasmic reticulum-associated degradation (ERAD). Next a synthetic gene array identifies nonessential genes that negatively regulate Kir2.1. The most prominent gene family that emerges from this effort encodes members of endosomal sorting complex required for transport (ESCRT). ERAD and ESCRT also mediate Kir2.1 degradation in human cells, with ESCRT playing a more prominent role. Thus multiple proteolytic pathways control Kir2.1 levels at the plasma membrane.
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15261 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Alexander R
AR
Kolb
Patrick G
PG
Needham
Cari
C
Rothenberg
Christopher J
CJ
Guerriero
Paul A
PA
Welling
Jeffrey L
JL
Brodsky
D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D013499:Surface Properties
D056827:Endosomal Sorting Complexes Required for Transport; C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying