Function of inhibitor of Bruton's tyrosine kinase isoform α (IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response

Abstract

Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR.

Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans

“…Antibodies targeting phosphoproteins were incubated with 1 mM sodium orthovanadate in 0.5% BSA/TBS. The following primary antibodies were used: 1:2,000 Vps15 for mouse studies (Novus Biologicals NBP1-30463) 39 , 1:1,000 VPS15 for human studies (Abcam ab124817, Abcam ab128903) 41 , 1:500 Vps34 (Cell Signaling, #3811) 42,43 , 1:1,000 Beclin1 (Cell Signaling #3738) 44 , 1:500 p62 (Novus Biologicals, H00008878-M01) 45 , 1:2,000 GAPDH (Millipore, MAB3 74) 26,46 , 1:1,000 ubiquitin (Santa Cruz, sc-8017) 47 , 1:10,000 α-tubulin (Sigma Aldrich, T6199) 48 , 1:100 LC3 (Nanotools, 0260-100/LC3-2G6) 49 , 1:600 EGFR (Cell Signaling #4267 S) 50 , 1:200 Nischarin (Santa Cruz, sc-365364) 21 , 1:500 PAK1 T423 (Cell Signaling, #2601 S) 51 and 1:500 N -terminal Vps15 antibody (Proteintech, 17894-1-AP). Western blots were quantified using ImageJ.…”

To die or not to die: death signaling in nonalcoholic fatty liver disease

“…For example, autophagy is induced to dispose of misfolded proteins remaining after ER-associated protein degradation [93]. Recently, Willy et al investigated an isoform of inhibitor of Burton’s tyrosine kinase (IBTKα) [94], a component of the UPR that resides mainly in the ER and is preferentially translated during ER stress [95]. They showed that IBTKα was up-regulated downstream of PERK-CHOP pathway during palmitate-induced ER stress [95], which was associated with aberrant autophagy linking to consequent inhibition of autophagic flux (Fig.…”

Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease

“…Normalization of ER stress markers correlated with weight loss and reduced hepatic lipid content after bariatric surgery (54). Furthermore, activation of the UPR was observed in the livers of obese patients with NASH as well as in mice fed a methionine-cholinedeficient diet (MCDD) exhibiting NASH features without obesity (55)(56)(57)(58). A direct activation of the IRE1α-XBP1 branch was observed in vivo during the development of insulin resistance in the liver (59).…”