Role of the ubiquitin system in regulating ion transport

Abstract

Ion channels and transporters play a critical role in ion and fluid homeostasis and thus in normal animal physiology and pathology. Tight regulation of these transmembrane proteins is therefore essential. In recent years, many studies have focused their attention on the role of the ubiquitin system in regulating ion channels and transporters, initialed by the discoveries of the role of this system in processing of Cystic Fibrosis Transmembrane Regulator (CFTR), and in regulating endocytosis of the epithelial Na + channel (ENaC) by the Nedd4 family of ubiquitin ligases (mainly Nedd4-2). In this review, we discuss the role of the ubiquitin system in ER Associated Degradation (ERAD) of ion channels, and in the regulation of endocytosis and lysosomal sorting of ion channels and transporters, focusing primarily in mammalian cells. We also briefly discuss the role of ubiquitin like molecules (such as SUMO) in such regulation, for which much less is known so far.

Derlin-1 promotes ubiquitylation and degradation of the epithelial Na+ channel, ENaC

“…This process begins with activation of the C-terminus of ubiquitin by an E1, transfer of ubiquitin to the conserved active site cysteine of an E2 through a transesterification reaction, and the relay of ubiquitin to a substrate via an E3 (Rotin and Staub, 2011). The substrate specificity for ubiquitin transfer to a target protein is conferred by the ubiquitin E3 ligases (Hurley and Stenmark, 2011).…”

“…The substrate specificity for ubiquitin transfer to a target protein is conferred by the ubiquitin E3 ligases (Hurley and Stenmark, 2011). Nedd4-2 (also known as NEDD4L) is an E3 ubiquitin ligase with a known involvement in the degradation of ENaC (Rotin and Staub, 2011). The yeast system requires Hrd1 and Doa10, two E3 ubiquitin ligases, to present a critical level of ubiquitin for effective targeting of ENaC for proteasome-mediated degradation, because the degradation and ubiquitylation of the ENaC subunits is suppressed by deletion of the genes encoding Hrd1 and Doa10 (Buck et al, 2010).…”

“…In the absence of α-ENaC, the β-ENaC and γ-ENaC subunits are degraded by the proteasome (Snyder, 2005;Staub et al, 1997;Valentijn et al, 1998). However, unlike the case for their well-investigated lysosomal degradation pathways, the underlying mechanism that leads to proteasomemediated degradation of ENaC subunits remains unclear (Ronzaud and Staub, 2014;Rotin and Staub, 2011).…”

Unique Regulation of Human Na+/H+ Exchanger 3 (NHE3) by Nedd4-2 Ligase That Differs from Non-primate NHE3s

“…Nedd4-1 (neural precursor cell expressed developmentally down-regulated 4-1) and Nedd4-2 belong to the Nedd4 family of E3 Ub ligases, which have an N-terminal C2 domain, three to four WW domains, and a C-terminal HECT domain (19,20). Nedd4 proteins typically interact with protein substrates through a PY (PPXY) motif.…”

Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

“…[23][24][25][26][27][28][29] The two genes interacting with EnaC are Nedd4L (neural precursor cell expressed, developmentally downregulated 4-like) and PRSS8 (prostasin). [30][31][32] The last group consists of three genes that are involved in CFTR trafficking, AHSAI (activator of heat shock 90-kDa protein ATPase homolog 1), CALR (calreticulin) and KRT19 (cytokeratin 19). [33][34][35][36] Most candidate gene and whole-genome association studies so far focused on time point measurements of only one or two lung function parameters.…”