The Batten disease gene CLN3 confers resistance to endoplasmic reticulum stress induced by tunicamycin.
Mutations in CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early-onset neurodegenerative disorder that is characterized by the accumulation of ceroid lipofuscin within lysosomes. The function of the CLN3 protein remains unclear and is presumed to be related to Endoplasmic reticulum (ER) stress. To investigate the function of CLN3 in the ER stress signaling pathway, we measured proliferation and apoptosis in cells transfected with normal and mutant CLN3 after treatment with the ER stress inducer tunicamycin (TM). We found that overexpression of CLN3 was sufficient in conferring increased resistance to ER stress. Wild-type CLN3 protected cells from TM-induced apoptosis and increased cell proliferation. Overexpression of wild-type CLN3 enhanced expression of the ER chaperone protein, glucose-regulated protein 78 (GRP78), and reduced expression of the proapoptotic protein CCAAT/-enhancer-binding protein homologous protein (CHOP). In contrast, overexpression of mutant CLN3 or siRNA knockdown of CLN3 produced the opposite effect. Together, our data suggest that the lack of CLN3 function in cells leads to a failure of management in the response to ER stress and this may be the key deficit in JNCL that causes neuronal degeneration.
Department of Medical Genetics, Peking University Health Science Center, No 38 Xueyuan Road, Haidian district, Beijing 100191, China. Electronic address: danw@bjmu.edu.cn.
Dan
D
Wu
Department of Medical Genetics, Peking University Health Science Center, No 38 Xueyuan Road, Haidian district, Beijing 100191, China.
Jing
J
Liu
Department of Medical Genetics, Peking University Health Science Center, No 38 Xueyuan Road, Haidian district, Beijing 100191, China.
Baiyan
B
Wu
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, No 38 Xueyuan Road, Haidian district, Beijing 100191, China.
Bo
B
Tu
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, No 38 Xueyuan Road, Haidian district, Beijing 100191, China.
Weiguo
W
Zhu
Department of Medical Genetics, Peking University Health Science Center, No 38 Xueyuan Road, Haidian district, Beijing 100191, China; Department of Medical and Research Technology, School of Medicine, University of Maryland, Baltimore 21201, USA. Electronic address: jluo@som.umaryland.edu.
Jianyuan
J
Luo
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D018832:Molecular Chaperones / Q000235:genetics* / Q000502:physiology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014415:Tunicamycin / Q000494:pharmacology*
C105199:CLN3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D014415:Tunicamycin; D051742:Transcription Factor CHOP
CLN3; Endoplasmic reticulum (ER) stress; JNCL; Tunicamycin