title: A pathogenic role for ER stress-induced autophagy and ER chaperone GRP78/BiP in T lymphocyte systemic lupus erythematosus.
abstract: Abnormal regulation of ER stress and apoptosis has been implicated in autoimmune disorders. Particularly, ER stress-induced autophagy and the role of GRP78, or BiP in T lymphocyte survival and death in SLE are poorly understood. This study investigated the pathogenic roles of ER stress-induced autophagy and GRP78/BiP in apoptosis of T lymphocytes. We compared spontaneous and induced autophagy and apoptosis of T lymphocytes in healthy donors and patients with SLE. The molecular mechanism of altered autophagy and apoptosis was investigated in T lymphocytes transfected with siRNA for beclin 1 and CHOP and T lymphocytes overexpressing GRP78. Decreased autophagy and increased apoptosis in response to TG-induced ER stress were observed in lupus T lymphocytes. GRP78 and ER stress-signaling molecules, such as PERK, p-eIF2α, IRE1, and ATF6 decreased, whereas CHOP levels increased in lupus T cells in response to TG. The levels antiapoptotic molecules, Bcl-2 and Bcl-XL decreased, whereas the proapoptotic molecules, Bax and caspase 6, increased in lupus T cells. The TG-induced ER stress altered autophagy and apoptosis, which in turn, led to abnormal T cell homeostasis with increased apoptotic T cell death. We hypothesize that aberrant autophagy of T lymphocytes as a result of ER stress and decreased GRP78 expression is involved in the pathogenesis of SLE and might serve as important therapeutic targets.
authors.affiliation: *Department of Internal Medicine, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University Hospital, and Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea; and Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Lee
authors.affiliation: *Department of Internal Medicine, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University Hospital, and Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea; and Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
authors.forename: Myung-Soon
authors.initials: MS
authors.lastname: Sung
authors.affiliation: *Department of Internal Medicine, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University Hospital, and Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea; and Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
authors.forename: Eun-Gyeong
authors.initials: EG
authors.lastname: Lee
authors.affiliation: *Department of Internal Medicine, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University Hospital, and Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea; and Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
authors.forename: Han-Gyul
authors.initials: HG
authors.lastname: Yoo
authors.affiliation: *Department of Internal Medicine, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University Hospital, and Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea; and Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
authors.forename: Yun-Hong
authors.initials: YH
authors.lastname: Cheon
authors.affiliation: *Department of Internal Medicine, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University Hospital, and Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea; and Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.
authors.forename: Han-Jung
authors.initials: HJ
authors.lastname: Chae
authors.affiliation: *Department of Internal Medicine, Chonbuk National University Medical School, and Research Institute of Clinical Medicine of Chonbuk National University Hospital, and Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, South Korea; and Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA ywhim@jbnu.ac.kr.
authors.forename: Wan-Hee
authors.initials: WH
authors.lastname: Yoo
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071186:Beclin-1; D053178:Caspase 6 / Q000235:genetics / Q000276:immunology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000276:immunology*; D004722:Endoribonucleases / Q000235:genetics / Q000276:immunology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000276:immunology; D051020:bcl-X Protein / Q000235:genetics / Q000276:immunology; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C505514:CASP6 protein, human; D053178:Caspase 6
keywords: SLE; T cells; apoptosis