S-Nitrosylation of CHIP Enhances F508Del CFTR Maturation.

S-Nitrosylation of CHIP Enhances F508Del CFTR Maturation. Am J Respir Cell Mol Biol. 2019 Oct 09;: Authors: Zaman K, Knight J, Hussain F, Cao R, Estabrooks SK, Altawallbeh G, Holloway K, Jafri A, Sawczak V, Li Y, Getsy P, Sun F, Raffay T, Cotton C, Brodsky JL, Periasamy A, Lewis SJ, Gaston B Abstract S-Nitrosothiols (SNOs) are endogenous signaling compounds with a diverse spectrum of beneficial airway effects that are both cGMP-dependent and -independent. SNOs are present in healthy human airways, but levels are low in the airways of cystic fibrosis (CF) patients. Here, we evaluated the interactions of SNOs with molecular co-chaperone C-terminus Hsc70 interacting protein (CHIP)- an E3 ubiquitin ligase that targets improperly folded CFTR for degradation. CHIP was expressed in primary human bronchial epithelial and CFBE41o - cells expressing either wild type or F508del CFTR. Confocal microscopy and immunoprecipitation studies showed the cellular co-localization of CFTR and CHIP and showed that GSNO inhibits the CHIP-CFTR interaction. SNOs significantly reduced both the expression and activity of CHIP, leading to higher levels of both the immature and mature forms of F508del CFTR; in fact, inhibition of the expression and function of CHIP by SNOs not only improved CFTR maturation, but also increased CFTR stability at the cell membrane. GSNO treated cells also had more S-nitrosylated CHIP and less ubiquitinated CFTR than untreated cells,...
Source: Am J Respir Cell Mol... - Category: Respiratory Medicine Authors: Tags: Am J Respir Cell Mol Biol Source Type: research