A SNARE protein Syntaxin 17 captures CFTR to potentiate autophagosomal clearance under stress

Abstract

Macroautophagy, or simply autophagy, is a catabolic program for restoring cellular resources and energy balance as cells recognize damaged organelles, protein aggregates, and invading pathogens. 1,2 As new studies emerge, the role of autophagy has been expanded to include cell growth, cell development and aging, tumor suppression, and immunity among others. 2 Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the lung and intestinal epithelial cells and forms a key transporter to regulate fluid transit across the epithelium. Deficiency of CFTR dependent function due to genetic alterations in the Cftr gene causes cystic fibrosis (CF). CF is a multi-organ disorder, while the lung remains the most impacted organ due to recurrent episodes of infection that leads to inflammation. The role of autophagy in CF is now becoming increasingly recognized with some evidence of impaired autophagic clearance in CF macrophages causing low bactericidal activity, aggresome formation, and therapeutic benefit of autophagy modulators in the CF epithelial cells. [3][4][5] Autophagy can be stimulated by nutritional deprivation and pathogen insult. 6 Autophagy begins with the formation of an isolation membrane (phagophore) at the endoplasmic reticulum (ER)-mitochondrial interface, 7 with subsequent sequestering of a portion of cytoplasm and damaged organelles as autophagic intermediates continue to grow and form enclosed, double-membraned structures called

Proximity Profiling of the CFTR Interaction Landscape in Response to Orkambi

“…Syntaxin 5 (STX5) overexpression has been shown to stimulate unconventional trafficking of core-glycosylated ∆F508-CFTR to the PM [ 35 ]. Syntaxin-17 (STX17), a SNARE protein, interacts with CFTR [ 52 ] and the loss of the CFTR-STX17 interaction impairs bacterial clearance and could play a critical role in infectious diseases among CF patients. Syntaxin-12 (STX12) and STX6 form a SNARE complex that regulates transport between late endosomes and the trans-Golgi network.…”

Ion Channels and Pumps in Autophagy: A Reciprocal Relationship

“…In this review, we aimed to discuss current knowledge of how distinct steps of the autophagy-lysosomal process are regulated by ion transporters ( Figure 1 ). For brevity, we mostly excluded tissue-specific ion channels such as the plasma membrane CFTR or ER-localized RyR, which are reported to influence autophagy in specific tissue types [ 159 , 160 ]. A few regulatory nodes become clear if we look at ion channel regulation of autophagy (summarized in Figure 1 ).…”

Emerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis

“…Macroautophagy (canonical autophagy) occurs inside a double membrane structure called an autophagosome. Multiple studies have demonstrated defective autophagy in CF phagocytes and other cells, with the critical restoration of macrophage properties through autophagy manipulation [ 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 ].…”

“…Syntax 17 (Stx17) is required for fusion with the lysosome; lack of Stx17 causes the accumulation of autophagosomes without degradation [ 166 ]. In a study conducted by Arora et al using epithelial cells, Stx17 was associated with CFTR at a late stage of autophagy to mediate bacterial clearance [ 133 ]. Whether these interactions are conserved in CF macrophages has not yet been determined.…”