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Lysosomal Ca 2+ contributes to macroautophagy/autophagy, an intracellular process for the degradation of cytoplasmic material and organelles in the lysosomes to protect cells against stress responses. TMBIM6 (transmembrane BAX inhibitor motif containing 6) is a Ca 2+ channel-like protein known to regulate ER stress response and apoptosis. In this study, we examined the as yet unknown role of TMBIM6 in regulating lysosomal Ca 2+ levels. The Ca 2+ efflux from the ER through TMBIM6 was found to increase the resting lysosomal Ca 2+ level, in which ITPR-independent regulation of Ca 2+ status was observed. Further, TMBIM6 regulated the local release of Ca 2+ through lysosomal MCOLN1/TRPML1 channels under nutrient starvation or MTOR inhibition. The local Ca 2+ efflux through MCOLN1 channels was found to activate PPP3/calcineurin, triggering TFEB (transcription factor EB) nuclear translocation, autophagy induction, and lysosome biogenesis. Upon genetic inactivation of TMBIM6, lysosomal Ca 2+ and the associated TFEB nuclear translocation were decreased. Furthermore, autophagy flux was significantly enhanced in the liver or kidney from starved Tmbim6 +/+ mice compared with that in the counter tmbim6 -/- mice. Together, our observations indicated that under stress conditions, TMBIM6 increases lysosomal Ca 2+ : AVs: autophagic vacuoles; CEPIA: calcium-measuring organelle-entrapped protein indicator; ER: endoplasmic reticulum; GPN: glycyl-L-phenylalanine-beta-naphthylamide; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; LAMP1: lysosomal associated membrane protein 1; MCOLN/TRPML: mucolipin; MEF: mouse embryonic fibroblast; ML-SA1: mucolipin synthetic agonist 1; MTORC1: mechanistic target of rapamycin kinase complex 1; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TKO: triple knockout; TMBIM6/BI-1: transmembrane BAX inhibitor motif containing 6.2+ modulator that coordinates with autophagy to alleviate metabolism stress. Abbreviations : AVs: autophagic vacuoles; CEPIA: calcium-measuring organelle-entrapped protein indicator; ER: endoplasmic reticulum; GPN: glycyl-L-phenylalanine-beta-naphthylamide; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; LAMP1: lysosomal associated membrane protein 1; MCOLN/TRPML: mucolipin; MEF: mouse embryonic fibroblast; ML-SA1: mucolipin synthetic agonist 1; MTORC1: mechanistic target of rapamycin kinase complex 1; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TKO: triple knockout; TMBIM6/BI-1: transmembrane BAX inhibitor motif containing 6.

Compromised protein folding capacity in the endoplasmic reticulum (ER) leads to a protein traffic jam that produces a toxic environment called ER stress. However, the ER smartly handles such a critical situation by activating a cascade of proteins responsible for sensing and responding to the noxious stimuli of accumulated proteins. The ER protein load is higher in secretory cells, such as liver hepatocytes, which are thus prone to stress-mediated toxicity and various diseases, including alcohol-induced liver injury, fatty liver disease, and viral hepatitis. Therefore, we discuss the molecular cues that connect ER stress to hepatic diseases. Moreover, we review the literature on ER stress-regulated miRNA in the pathogenesis of liver diseases to give a comprehensive overview of mechanistic insights connecting ER stress and miRNA in the context of liver diseases. We also discuss currently discovered regulated IRE1 dependent decay in regulation of hepatic diseases., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Study Question: Is the Transmembrane BAX Inhibitor Motif-6 (TMBIM6) involved in the molecular mechanism by which cisplatin causes reproductive toxicity?Summary Answer: TMBIM6 protects against cisplatin-induced testicular toxicity through up-regulation of heme oxygenase-1 (HO-1),-which maintains the levels of steroidogenic enzymes by decreaseing oxidative stress in the endoplasmic reticulum (ER).What Is Known Already: Testosterone production is highly suppressed as a main complication of cisplatin (cis-diamminedichloroplatinum) anticancer therapy.Study Design, Size, Duration: Groups of seven wild type or Tmbim6 KO C57BL/6J mice were given a single i.p., injection of cisplatin (30 mg/kg body wt) and testis and serum were collected 3 days later. Tmbim6-lentivirus-mediated testicular expression-rescued KO mice were analyzed to confirm function was restored. Tmbim6-over expressing TM3 mouse Leydig cells were exposed to cisplatin in vitro.Participants/materials, Setting, Methods: After collection of the specimens serum testosterone level and testicular weight and structure were compared between the groups. Quantitative PCR, immunoblot, and assays for ROS, HO-1 activity and protein disulfide isomerase (PDI) carbonylation were performed.Main Results and the Role Of Chance: Phospho protein kinase B (p-Akt), nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), and its downstream gene product HO-1 and the levels of testosterone synthesis-associated enzymes, including steroidogenic acute regulatory protein (StAR), a rate limiting enzyme for testosterone production, were significantly expressed in the presence of Tmbim6 and maintained after cisplatin treament. Excessive post-translational oxidation of protein disulfide isomerase (PDI), altered folding capacitance and ROS accumulation, and ER stress were also decreased in the presence of Tmbim6. Higher levels of ER stress and protein hypercarbonylation were consistently observed in KO testis, compared with WT testis. In the Tmbim6 KO mice, lentivirus-mediated testicular expression of Tmbim6 rescued the above phenotypes. Furthermore, the protective role of Tmbim6 against testicular toxicity was consistently shown in Tmbim6-overexpressing TM3 Leydig cells (testosterone producing cells). We conclude that TMBIM6 protects against cisplatin-induced testicular toxicity by inducing HO-1 and enhancing ER folding capacitance.Large Scale Data: N/A.Limitations, Reasons For Caution: This study was performed using a short, 3-day cisplatin treatment condition. Therefore, the results need to be cautiously interpreted with regard to cisplatin-associated chronic toxicity. Moreover, to determine the clinical relevance of the role of TMBIM6, further studies in testicular cancer are needed.Wider Implications Of the Findings: Cisplatin-associated ER stress and redox imbalance might be implicated as toxicity mechanisms associated with anticancer therapy.Study Funding/competing Interest(s): This study was supported by the National Research Foundation of Korea (2015R1A2A1A13001849). The authors have no competing interests to disclose. [ABSTRACT FROM AUTHOR]