Nardilysin Is Required for Maintaining Pancreatic β-Cell Function

Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). Several transcription factors enriched in β-cells, such as MafA, control β-cell function by organizing genes involved in GSIS. Here we demonstrate that nardilysin (N-arginine dibasic convertase; Nrd1 and NRDc) critically regulates β-cell function through MafA. Nrd1−/− mice showed glucose intolerance and severely decreased GSIS. Islets isolated from Nrd1−/− mice exhibited reduced insulin content and impaired GSIS in vitro. Moreover, β-cell-specific NRDc-deficient (Nrd1delβ) mice showed a diabetic phenotype with markedly reduced GSIS. MafA was specifically downregulated in islets from Nrd1delβ mice, whereas overexpression of NRDc upregulated MafA and insulin expression in INS832/13 cells. Chromatin immunoprecipitation assay revealed that NRDc is associated with Islet-1 in the enhancer region of MafA, where NRDc controls the recruitment of Islet-1 and MafA transcription. Our findings demonstrate that NRDc controls β-cell function via regulation of the Islet-1–MafA pathway.

[1]  D. Accili,et al.  Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes. , 2016, The Journal of clinical endocrinology and metabolism.

[2]  J. Prins,et al.  Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes. , 2016, Journal of molecular endocrinology.

[3]  P. Thorn,et al.  Insulin secretion from beta cells within intact islets: Location matters , 2015, Clinical and experimental pharmacology & physiology.

[4]  Satoru Takahashi,et al.  MafA is critical for maintenance of the mature beta cell phenotype in mice , 2015, Diabetologia.

[5]  J. Schug,et al.  Islet-1 Is Essential for Pancreatic β-Cell Function , 2014, Diabetes.

[6]  Satoru Takahashi,et al.  MafA Is Required for Postnatal Proliferation of Pancreatic β-Cells , 2014, PloS one.

[7]  H. Seno,et al.  Deletion of Nardilysin Prevents the Development of Steatohepatitis and Liver Fibrotic Changes , 2014, PloS one.

[8]  W. Bush,et al.  The MafA Transcription Factor Becomes Essential to Islet β-Cells Soon After Birth , 2014, Diabetes.

[9]  Takeshi Kimura,et al.  Critical roles of nardilysin in the maintenance of body temperature homoeostasis , 2014, Nature Communications.

[10]  Changhong Li,et al.  Pdx1 maintains β cell identity and function by repressing an α cell program. , 2014, Cell metabolism.

[11]  R. Takahashi,et al.  Nardilysin prevents amyloid plaque formation by enhancing α-secretase activity in an Alzheimer's disease mouse model , 2014, Neurobiology of Aging.

[12]  Hiroki Sato,et al.  Palmitate induces reactive oxygen species production and β‐cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling , 2013, Journal of diabetes investigation.

[13]  M. Sander,et al.  Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. , 2013, Cell reports.

[14]  Maike Sander,et al.  Inactivation of specific β cell transcription factors in type 2 diabetes. , 2013, The Journal of clinical investigation.

[15]  R. Stein,et al.  Characterization of an Apparently Novel β-Cell Line-enriched 80–88 kDa Transcriptional Activator of the MafA and Pdx1 Genes* , 2012, The Journal of Biological Chemistry.

[16]  C. Talchai,et al.  Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure , 2012, Cell.

[17]  F. Ashcroft,et al.  Diabetes Mellitus and the β Cell: The Last Ten Years , 2012, Cell.

[18]  Jun Qin,et al.  Identification and Characterization of Nardilysin as a Novel Dimethyl H3K4-binding Protein Involved in Transcriptional Regulation* , 2012, The Journal of Biological Chemistry.

[19]  R. Stein,et al.  MafA and MafB activity in pancreatic β cells , 2011, Trends in Endocrinology & Metabolism.

[20]  S. Bonner-Weir,et al.  Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells , 2011, Diabetologia.

[21]  H. Masutani,et al.  Disruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity , 2010, Nature communications.

[22]  L. Sussel,et al.  Islet β-Cell-Specific MafA Transcription Requires the 5′-Flanking Conserved Region 3 Control Domain , 2010, Molecular and Cellular Biology.

[23]  K. Kaestner,et al.  Pancreatic beta cells require NeuroD to achieve and maintain functional maturity. , 2010, Cell metabolism.

[24]  H. Kiyonari,et al.  Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system , 2009, Nature Neuroscience.

[25]  Ping Chen,et al.  The LIM-homeodomain protein ISL1 activates insulin gene promoter directly through synergy with BETA2. , 2009, Journal of molecular biology.

[26]  R. Stein,et al.  Islet-1 is Required for the Maturation, Proliferation, and Survival of the Endocrine Pancreas , 2009, Diabetes.

[27]  T. Kita,et al.  Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases. , 2008, Biochemical and biophysical research communications.

[28]  A. Houllier,et al.  Loss of Sugar Detection by GLUT2 Affects Glucose Homeostasis in Mice , 2007, PloS one.

[29]  T. Kita,et al.  Enhancement of α‐secretase cleavage of amyloid precursor protein by a metalloendopeptidase nardilysin , 2007, Journal of neurochemistry.

[30]  M. Moss,et al.  Fluorescent substrates for the proteinases ADAM17, ADAM10, ADAM8, and ADAM12 useful for high-throughput inhibitor screening. , 2007, Analytical biochemistry.

[31]  T. Kita,et al.  Nardilysin Enhances Ectodomain Shedding of Heparin-binding Epidermal Growth Factor-like Growth Factor through Activation of Tumor Necrosis Factor-α-converting Enzyme* , 2006, Journal of Biological Chemistry.

[32]  L. Sussel,et al.  FoxA2, Nkx2.2, and PDX-1 Regulate Islet β-Cell-Specific mafA Expression through Conserved Sequences Located between Base Pairs −8118 and −7750 Upstream from the Transcription Start Site , 2006, Molecular and Cellular Biology.

[33]  Ji-yeon Lee,et al.  RIP-Cre Revisited, Evidence for Impairments of Pancreatic β-Cell Function* , 2006, Journal of Biological Chemistry.

[34]  J. D. Engel,et al.  MafA Is a Key Regulator of Glucose-Stimulated Insulin Secretion , 2005, Molecular and Cellular Biology.

[35]  T. Matsuoka,et al.  The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Kataoka,et al.  MafA Is a Glucose-regulated and Pancreatic β-Cell-specific Transcriptional Activator for the Insulin Gene* , 2002, The Journal of Biological Chemistry.

[37]  A. Prat,et al.  The metalloendopeptidase nardilysin (NRDc) is potently inhibited by heparin-binding epidermal growth factor-like growth factor (HB-EGF). , 2002, The Biochemical journal.

[38]  A. Prat,et al.  N‐arginine dibasic convertase is a specific receptor for heparin‐binding EGF‐like growth factor that mediates cell migration , 2001, The EMBO journal.

[39]  Shankar Srinivas,et al.  Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus , 2001, BMC Developmental Biology.

[40]  B. Thorens,et al.  Glucose uptake, utilization, and signaling in GLUT2-null islets. , 2000, Diabetes.

[41]  I. Bach,et al.  The LIM domain: regulation by association , 2000, Mechanisms of Development.

[42]  M. Prentki,et al.  Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. , 2000, Diabetes.

[43]  M. Magnuson,et al.  Dual Roles for Glucokinase in Glucose Homeostasis as Determined by Liver and Pancreatic β Cell-specific Gene Knock-outs Using Cre Recombinase* , 1999, The Journal of Biological Chemistry.

[44]  H. Edlund,et al.  beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. , 1998, Genes & development.

[45]  M. Birnbaum,et al.  Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2 , 1997, Nature Genetics.

[46]  L. Jurata,et al.  Functional analysis of the nuclear LIM domain interactor NLI , 1997, Molecular and cellular biology.

[47]  A. Prat,et al.  N-arginine dibasic convertase, a metalloendopeptidase as a prototype of a class of processing enzymes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  H. A. Louis,et al.  Structure of the carboxy-terminal LIM domain from the cysteine rich protein CRP , 1994, Nature Structural Biology.

[49]  C. Créminon,et al.  Isolation and characterization of a dibasic selective metalloendopeptidase from rat testes that cleaves at the amino terminus of arginine residues. , 1994, The Journal of biological chemistry.

[50]  Y Ikawa,et al.  A novel ES cell line, TT2, with high germline-differentiating potency. , 1993, Analytical biochemistry.

[51]  J. Miyazaki,et al.  Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. , 1990, Endocrinology.

[52]  R. Stein,et al.  Inactivation of specific b cell transcription factors in type 2 diabetes , 2018 .