title: Sublethal endoplasmic reticulum stress caused by the mutation of immunoglobulin heavy chain-binding protein induces the synthesis of a mitochondrial protein, pyrroline-5-carboxylate reductase 1.
abstract: Most human neurodegenerative diseases are sporadic and appear later in life. Aging and neurodegeneration are closely associated, and recent investigations reveal that endoplasmic reticulum (ER) stress is involved in the progression of these features. Immunoglobulin heavy chain-binding protein (BiP) is an ER chaperone that is central to ER functions. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence to elucidate the effect of a functional defect in an ER chaperone in multicellular organisms. The homozygous mutant BiP mice died within several hours after birth because of respiratory failure with an impaired biosynthesis of pulmonary surfactant by alveolar type II cells. The heterozygous mutant BiP mice grew up to be apparently normal adults, although some of them revealed motor disabilities as they aged. Here, we report that the synthesis of a mitochondrial protein, pyrroline-5-carboxylate reductase 1 (PYCR1), is enhanced in the brains of homozygous mutant BiP mice. We performed a two-dimensional gel analysis followed by liquid chromatography-tandem mass spectrometry. PYCR1 was identified as one of the enhanced proteins. We also found that sublethal ER stress caused by tunicamycin treatment induced the synthesis of PYCR1 in murine fibroblasts. PYCR1 has been shown to be related to the aging process. Mutations in the PYCR1 gene cause cutis laxa with progeroid features and mental retardation. These findings suggest a pathophysiological interaction between ER stress and a mitochondrial function in aging.
authors: Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.|Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
authors: Hisayo
authors: H
authors: Jin
authors: Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.
authors: Mari
authors: M
authors: Komita
authors: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
authors: Haruhiko
authors: H
authors: Koseki
authors: Pain Center, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara City, Chiba, 299-0111, Japan. tomohikoA@aol.com.
authors: Tomohiko
authors: 0000-0002-2729-9394
authors: T
authors: Aoe
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D015180:Electrophoresis, Gel, Two-Dimensional; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055879:Gene Knock-In Techniques; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D016296:Mutagenesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011762:Pyrroline Carboxylate Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014415:Tunicamycin / Q000633:toxicity; D019892:eIF-2 Kinase / Q000378:metabolism; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011762:Pyrroline Carboxylate Reductases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014415:Tunicamycin; D019892:eIF-2 Kinase; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase; C497112:Atf6 protein, mouse; C486556:Ern2 protein, mouse
keywords: Aging; Chaperone; ER stress; Mitochondria; UPR