title: Cathepsin B contributes to autophagy-related 7 (Atg7)-induced nod-like receptor 3 (NLRP3)-dependent proinflammatory response and aggravates lipotoxicity in rat insulinoma cell line.
abstract: Impairment of glucose-stimulated insulin secretion caused by the lipotoxicity of palmitate was found in β-cells. Recent studies have indicated that defects in autophagy contribute to pathogenesis in type 2 diabetes. Here, we report that autophagy-related 7 (Atg7) induced excessive autophagic activation in INS-1(823/13) cells exposed to saturated fatty acids. Atg7-induced cathepsin B (CTSB) overexpression resulted in an unexpected significant increase in proinflammatory chemokine and cytokine production levels of IL-1β, monocyte chemotactic protein-1, IL-6, and TNF-α. Inhibition of receptor-interacting protein did not affect the inflammatory response, ruling out involvement of necrosis. CTSB siRNA suppressed the inflammatory response but did not affect apoptosis significantly, suggesting that CTSB was a molecular linker between autophagy and the proinflammatory response. Blocking caspase-3 suppressed apoptosis but did not affect the inflammatory response, suggesting that CTSB induced inflammatory effects independently of apoptosis. Silencing of Nod-like receptor 3 (NLRP3) completely abolished both IL-1β secretion and the down-regulation effects of Atg7-induced CTSB overexpression on glucose-stimulated insulin secretion impairment, thus identifying the NLRP3 inflammasome as an autophagy-responsive element in the pancreatic INS-1(823/13) cell line. Combined together, our results indicate that CTSB contributed to the Atg7-induced NLRP3-dependent proinflammatory response, resulting in aggravation of lipotoxicity, independently of apoptosis in the pancreatic INS-1(823/13) cell line.
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Shali
authors.initials: S
authors.lastname: Li
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Du
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Hu
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Wenchun
authors.initials: W
authors.lastname: Xia
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Fengqi
authors.initials: F
authors.lastname: Zhu
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China.
authors.forename: Chunxian
authors.initials: C
authors.lastname: Li
authors.affiliation: From the Department of Cell Biology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu Province 210046, China. Electronic address: 08275@njnu.edu.cn.
authors.forename: SiJun
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D000071193:Autophagy-Related Protein 7; D002352:Carrier Proteins; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism*
chemical_list: C561242:Atg7 protein, rat; D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D002401:Cathepsin B; C533916:Ctsb protein, rat; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D005947:Glucose
keywords: Autophagy; Cytokine; Glucose Metabolism; Inflammation; Insulin Resistance; Pancreatic Islets