Endoplasmic reticulum-stress and unfolded protein response-activation in immune-mediated necrotizing myopathy

被引:10
作者
Preusse, Corinna [1 ,2 ,3 ,4 ]
Marteau, Theodore [5 ]
Fischer, Norina [1 ,2 ,3 ]
Hentschel, Andreas [6 ]
Sickmann, Albert [6 ]
Lang, Sven [7 ]
Schneider, Udo [2 ,3 ,8 ]
Schara-Schmidt, Ulrike [5 ]
Meyer, Nancy [5 ]
Ruck, Tobias [9 ]
Dengler, Nora F. [2 ,3 ,10 ]
Prudlo, Johannes [11 ,12 ,13 ]
Dudesek, Ales [11 ]
Gorl, Norman [14 ]
Allenbach, Yves [15 ]
Benveniste, Olivier [15 ]
Goebel, Hans-Hilmar [1 ,2 ,3 ,16 ]
Dittmayer, Carsten [1 ,2 ,3 ]
Stenzel, Werner [1 ,2 ,3 ]
Roos, Andreas [5 ,17 ]
机构
[1] Charite Univ Med Berlin, Dept Neuropathol, Charitepl 1, D-10117 Berlin, Germany
[2] Free Univ Berlin, Berlin, Germany
[3] Humboldt Univ, Berlin, Germany
[4] Univ Hosp Munster, Dept Neurol, Inst Translat Neurol, Munster, Germany
[5] Univ Duisburg Essen, Univ Childrens Hosp, Fac Med, Pediat Neurol, Essen, Germany
[6] Leibniz Inst Analyt Wissensch ISAS eV, Dortmund, Germany
[7] Saarland Univ, Dept Med Biochem & Mol Biol, Homburg, Germany
[8] Charite Univ Med Berlin, Dept Rheumatol, Berlin, Germany
[9] Heinrich Heine Univ, Med Fac, Dept Neurol, Dusseldorf, Germany
[10] Charite Univ Med Berlin, Dept Neurosurg, Berlin, Germany
[11] Rostock Univ, Dept Neurol, Med Ctr, Rostock, Germany
[12] German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Rostock, Germany
[13] Univ Rostock, Dept Neurol, Rostock, Germany
[14] Klinikum Sudstadt Rostock, Dept Internal Med, Rostock, Germany
[15] Sorbonne Univ, Pitie Salpetriere Univ Hosp, AP HP, Dept Internal Med & Clin Immunol, Paris, France
[16] Univ Hosp Mainz, Dept Neuropathol, Mainz, Germany
[17] Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
关键词
auto-antibodies; ER-stress; HMGCR; IMNM; SRP; UPR; ER STRESS; CLASSIFICATION; AUTOPHAGY; BIP;
D O I
10.1111/bpa.13084
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Patients suffering from immune-mediated necrotizing myopathies (IMNM) harbor, the pathognomonic myositis-specific auto-antibodies anti-SRP54 or -HMGCR, while about one third of them do not. Activation of chaperone-assisted autophagy was described as being part of the molecular etiology of IMNM. Endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR)-stress accompanied by activation of the unfolded protein response (UPR) often precedes activation of the protein clearance machinery and represents a cellular defense mechanism toward restoration of proteostasis. Here, we show that ER/SR-stress may be part of the molecular etiology of IMNM. To address this assumption, ER/SR-stress related key players covering the three known branches (PERK-mediated, IRE1-mediated, and ATF6-mediated) were investigated on both, the transcript and the protein levels utilizing 39 muscle biopsy specimens derived from IMNM-patients. Our results demonstrate an activation of all three UPR-branches in IMNM, which most likely precedes the activation of the protein clearance machinery. In detail, we identified increased phosphorylation of PERK and eIF2a along with increased expression and protein abundance of ATF4, all well-documented characteristics for the activation of the UPR. Further, we identified increased general XBP1-level, and elevated XBP1 protein levels. Additionally, our transcript studies revealed an increased ATF6-expression, which was confirmed by immunostaining studies indicating a myonuclear translocation of the cleaved ATF6-form toward the forced transcription of UPR-related chaperones. In accordance with that, our data demonstrate an increase of downstream factors including ER/SR co-chaperones and chaperones (e.g., SIL1) indicating an UPR-activation on a broader level with no significant differences between seropositive and seronegative patients. Taken together, one might assume that UPR-activation within muscle fibers might not only serve to restore protein homeostasis, but also enhance sarcolemmal presentation of proteins crucial for attracting immune cells. Since modulation of ER-stress and UPR via application of chemical chaperones became a promising therapeutic treatment approach, our findings might represent the starting point for new interventional concepts.
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页数:15
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