SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology
Mutations in SIL1, a cofactor for the endoplasmic reticulum (ER)-localized Hsp70 chaperone, BiP, cause Marinesco-Sjögren syndrome (MSS), an autosomal recessive disorder. Using a mouse model, we characterized molecular aspects of the progressive myopathy associated with MSS. Proteomic profiling of qu...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2018-05-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/11/5/dmm033043 |
| _version_ | 1818585651536199680 |
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| author | Viraj P. Ichhaporia Jieun Kim Kanisha Kavdia Peter Vogel Linda Horner Sharon Frase Linda M. Hendershot |
| author_facet | Viraj P. Ichhaporia Jieun Kim Kanisha Kavdia Peter Vogel Linda Horner Sharon Frase Linda M. Hendershot |
| author_sort | Viraj P. Ichhaporia |
| collection | DOAJ |
| description | Mutations in SIL1, a cofactor for the endoplasmic reticulum (ER)-localized Hsp70 chaperone, BiP, cause Marinesco-Sjögren syndrome (MSS), an autosomal recessive disorder. Using a mouse model, we characterized molecular aspects of the progressive myopathy associated with MSS. Proteomic profiling of quadriceps at the onset of myopathy revealed that SIL1 deficiency affected multiple pathways critical to muscle physiology. We observed an increase in ER chaperones prior to the onset of muscle weakness, which was complemented by upregulation of multiple components of cellular protein degradation pathways. These responses were inadequate to maintain normal expression of secretory pathway proteins, including insulin and IGF-1 receptors. There was a paradoxical enhancement of downstream PI3K-AKT-mTOR signaling and glucose uptake in SIL1-disrupted skeletal muscles, all of which were insufficient to maintain skeletal muscle mass. Together, these data reveal a disruption in ER homeostasis upon SIL1 loss, which is countered by multiple compensatory responses that are ultimately unsuccessful, leading to trans-organellar proteostasis collapse and myopathy. |
| first_indexed | 2024-12-16T08:40:28Z |
| format | Article |
| id | doaj.art-f28ca7942d714c9ca1771367cfca05f3 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-16T08:40:28Z |
| publishDate | 2018-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-f28ca7942d714c9ca1771367cfca05f32022-12-21T22:37:41ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-05-0111510.1242/dmm.033043033043SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiologyViraj P. Ichhaporia0Jieun Kim1Kanisha Kavdia2Peter Vogel3Linda Horner4Sharon Frase5Linda M. Hendershot6 Dept of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA Small Animal Imaging Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Dept of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Dept of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA Mutations in SIL1, a cofactor for the endoplasmic reticulum (ER)-localized Hsp70 chaperone, BiP, cause Marinesco-Sjögren syndrome (MSS), an autosomal recessive disorder. Using a mouse model, we characterized molecular aspects of the progressive myopathy associated with MSS. Proteomic profiling of quadriceps at the onset of myopathy revealed that SIL1 deficiency affected multiple pathways critical to muscle physiology. We observed an increase in ER chaperones prior to the onset of muscle weakness, which was complemented by upregulation of multiple components of cellular protein degradation pathways. These responses were inadequate to maintain normal expression of secretory pathway proteins, including insulin and IGF-1 receptors. There was a paradoxical enhancement of downstream PI3K-AKT-mTOR signaling and glucose uptake in SIL1-disrupted skeletal muscles, all of which were insufficient to maintain skeletal muscle mass. Together, these data reveal a disruption in ER homeostasis upon SIL1 loss, which is countered by multiple compensatory responses that are ultimately unsuccessful, leading to trans-organellar proteostasis collapse and myopathy.http://dmm.biologists.org/content/11/5/dmm033043SIL1Endoplasmic reticulumMarinesco-Sjögren syndromeMyopathyProteostasis collapsePI3K-AKT-mTOR signaling |
| spellingShingle | Viraj P. Ichhaporia Jieun Kim Kanisha Kavdia Peter Vogel Linda Horner Sharon Frase Linda M. Hendershot SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology Disease Models & Mechanisms SIL1 Endoplasmic reticulum Marinesco-Sjögren syndrome Myopathy Proteostasis collapse PI3K-AKT-mTOR signaling |
| title | SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology |
| title_full | SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology |
| title_fullStr | SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology |
| title_full_unstemmed | SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology |
| title_short | SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology |
| title_sort | sil1 the endoplasmic reticulum localized bip co chaperone plays a crucial role in maintaining skeletal muscle proteostasis and physiology |
| topic | SIL1 Endoplasmic reticulum Marinesco-Sjögren syndrome Myopathy Proteostasis collapse PI3K-AKT-mTOR signaling |
| url | http://dmm.biologists.org/content/11/5/dmm033043 |
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