Dataset Information

SIL1 deficiency in lymphoblastoid cells: antagonizing cellular mechanisms and insights into selective vulnerability in Marinesco-Sjögren syndrome

ABSTRACT: Patients with Marinesco-Sjögren syndrome and gene targeting in mice revealed an essential role for the SIL1/Sil1 gene in maintenance of central nervous tissue and skeletal muscle. SIL1/Sil1 expression is not restricted to a certain tissue, and the gene product, SIL1/Sil1, localizes to the (sarco)endoplasmic reticulum. Due to the ADP/ATP exchange activity of SIL1/Sil1 for the major chaperone BiP (GRP78) it functions as a co-chaperone. It is still an enigma how loss of functional SIL1/Sil1 can lead to selective vulnerability of the nervous system and skeletal muscle whereas other cellular populations like lymphoblastoid cells (LCs) are protected against clinical manifestation of SIL1/Sil1 deficiency. In this study we address this issue in order to identify compensatory strategies and to gain a deeper understanding of the selective vulnerability in SIL1 pathology. By studying the morphology of SIL1-deficient LCs, we demonstrate that they present with altered organelle structures indicating subclinical vulnerability and once more the assumed presence of cellular strategies antagonizing phenotypical manifestation of loss of this co-chaperone. Proteomic profiling of MSS-derived LCs revealed affection of nuclear and mitochondrial integrity, cytoskeleton and cellular viability. Apart from that proteins, known to be causative for hereditary neuromuscular disorders or to be involved in development and function of the nervous system were altered in expression. Paradigmatic findings were confirmed in spleen of Sil1 deficient mice in comparison to appropriate controls. These findings along with the results of viability assays and the identification of activation of pro-survival mechanisms provide insights into cellular strategies antagonizing SIL1/Sil1 deficiency and on a more general note into the molecular cause of selective vulnerability defining the SIL1/Sil1-phenotype, in both man and mouse.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Obsolete Lymphoblast

SUBMITTER: Laxmikanth Kollipara

LAB HEAD: René Peiman Zahedi

PROVIDER: PXD003030 | Pride | 2017-10-10

REPOSITORIES: Pride

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In-depth phenotyping of lymphoblastoid cells suggests selective cellular vulnerability in Marinesco-Sjögren syndrome.

Kollipara Laxmikanth L Buchkremer Stephan S Coraspe José Andrés González JAG Hathazi Denisa D Senderek Jan J Weis Joachim J Zahedi René P RP Roos Andreas A

Oncotarget 20170728 40

SIL1 is a ubiquitous protein of the Endoplasmic Reticulum (ER) acting as a co-chaperone for the ER-resident chaperone, BiP. Recessive mutations of the corresponding gene lead to vulnerability of skeletal muscle and central nervous system in man (Marinesco-Sjögren syndrome; MSS) and mouse. However, it is still unclear how loss of ubiquitous SIL1 leads to selective vulnerability of the nervous system and skeletal muscle whereas other cells and organs are protected from clinical manifestations. In ...[more]

PMID: 28978133

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Project description:SIL1 acts as a co-chaperone for the major ER-resident chaperone BiP and thus plays a role in many BiP-dependent cellular functions such as protein folding control and unfolded protein response. Whereas increase of BiP upon cellular stress conditions is a well-known phenomenon, elevation of SIL1 under stress conditions was thus far solely studied in yeast and different studies indicated an adverse effect of SIL1 increase. This is seemingly in contrast with the beneficial effect of SIL1 increase in surviving neurons in neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and Alzheimer disease. In the present study, we systematically addressed these controversial findings. Using cell biological, morphological and biochemical methods, we could demonstrate that that SIL1 is increased in various mammalian cells and neuronal tissues upon induction of cellular stress. Investigation of heterozygous SIL1/Sil1 mutant cells and tissues supported this finding. Moreover, SIL1 protein was found to be stabilized during ER stress. Increased SIL1 initiates ER stress in a concentration-dependent manner which is in accordance with the described adverse effect of increased SIL1. However, our results also suggest that protective levels are achieved by the secretion of excessive SIL1 and GRP170 (no longer perturbing ER homeostasis) and that moderately increased SIL1 also ameliorates cellular fitness under stress conditions. Results of our immunoprecipitation studies indicate that under cellular stress conditions SIL1 might act in a BiP-independent manner. Unbiased proteomic studies revealed that elevated SIL1 levels alter the expression of several proteins including crucial players in neurodegeneration, especially in Alzheimer disease. This finding is in accordance with our observation of increased SIL1-immunoreactivity in surviving neurons of Alzheimer disease autopsy cases and supports the assumption that SIL1 plays a protective role in neurodegenerative disorders.

Project description:We used Affymetrix microarray profiling to analyze gene expression patterns in healthy donor liver as well as tumor and paired non-tumor tissue of HCC patients. For gene expression profiling, tumors and paired non-tumor tissues were profiled separately using a single channel array platform. Tumor and paired non-tumor samples of 22 patients of cohort1 and the normal liver pool were carried out on Affymetrix GeneChip HG-U133A 2.0 arrays (Affymetrix, Santa Clara, CA) according to the manufacturer's protocol. The fluorescent intensities were determined with an Affymetrix GeneChip Scanner 3000, controlled by GCOS Affymetrix software. All samples of cohort2 and 42 tumor and paired non-tumor samples of cohort2 were processed on the 96 HT HG-U133A microarray platform. The fluorescent intensities were determined with an Affymetrix GeneChip HT Array Plate Scanner, controlled by GCOS Affymetrix software. Cohort 1 Training Group: LCS-005A, LCS-019A, LCS-029A, LCS-039A, LCS-039B, LCS-254A, LCS-254B, LCS-068A, LCS-068B, LCS-076A, LCS-076B, LCS-004A, LCS-004B, LCS-007A, LCS-007B, LCS-024B, LCS-042B, LCS-062B, LCS-023A, LCS-023B, LCS-067A, LCS-065A, LCS-073A, LCS-067B, LCS-065B, LCS-073B, LCS-024A, LCS-042A, LCS-062A, LCS-015A, LCS-069A, LCS-015B, LCS-069B, LCS-033A, LCS-061A, LCS-020A, LCS-045A, LCS-033B, LCS-020B, LCS-045B, LCS-057A, LCS-009A, LCS-057B, LCS-009B, LCS-049A, LCS-049B, LCS-061B, LCS-047A, LCS-047B, LCS-075A, LCS-075B, LCS-034A, LCS-034B, LCS-041A, LCS-041B, LCS-044A, LCS-044B, LCS-071A, LCS-071B, LCS-036A, LCS-064A, LCS-064B, LCS-038A, LCS-038B, LCS-002A, LCS-028B, LCS-016B, LCS-054A, LCS-063A, LCS-022A, LCS-054B, LCS-063B, LCS-022B, LCS-036B, LCS-025A, LCS-066A, LCS-027A, LCS-048A, LCS-012A, LCS-025B, LCS-066B, LCS-027B, LCS-048B, LCS-012B, LCS-051A, LCS-056A, LCS-051B, LCS-056B, LCS-028A, LCS-016A, LCS-196A, LCS-196B, LCS-072A, LCS-072B, LCS-333A, LCS-333B, LCS-339A, LCS-339B, LCS-341A, LCS-341B, LCS-343A, LCS-343B, LCS-344A, LCS-344B, LCS-346A, LCS-346B, LCS-347A, LCS-347B, LCS-393A, LCS-393B, LCS-400A, LCS-400B, LCS-401A, LCS-401B, LCS-403A, LCS-403B, LCS-406A, LCS-406B, LCS-415A, LCS-415B, LCS-424A, LCS-424B, LCS-426A, LCS-426B Cohort 2 Testing Group: LCS-079A, LCS-092A, LCS-101A, LCS-079B, LCS-092B, LCS-101B, LCS-083A, LCS-095A, LCS-102A, LCS-083B, LCS-095B, LCS-102B, LCS-085A, LCS-096A, LCS-103A, LCS-085B, LCS-096B, LCS-103B, LCS-091A, LCS-099A, LCS-105A, LCS-091B, LCS-099B, LCS-105B, LCS-122A, LCS-130A, LCS-123A, LCS-135A, LCS-123B, LCS-135B, LCS-125A, LCS-127A, LCS-136A, LCS-125B, LCS-127B, LCS-136B, LCS-122B, LCS-130B, LCS-212B, LCS-180B, LCS-183B, LCS-153B, LCS-018B, LCS-188A, LCS-185A, LCS-154A, LCS-120A, LCS-286A, LCS-086A, LCS-177A, LCS-140A, LCS-035A, LCS-188B, LCS-185B, LCS-154B, LCS-120B, LCS-286B, LCS-238B, LCS-086B, LCS-177B, LCS-035B, LCS-275B, LCS-132A, LCS-205A, LCS-274A, LCS-159A, LCS-150A, LCS-014A, LCS-227A, LCS-283A, LCS-162A, LCS-104A, LCS-272A, LCS-132B, LCS-205B, LCS-274B, LCS-159B, LCS-227B, LCS-046B, LCS-283B, LCS-272B, LCS-237A, LCS-152A, LCS-209A, LCS-211A, LCS-230A, LCS-262A, LCS-144A, LCS-158B, LCS-237B, LCS-152B, LCS-209B, LCS-211B, LCS-230B, LCS-262B, LCS-144B, LCS-212A, LCS-180A, LCS-183A, LCS-153A, LCS-018A, LCS-275A, LCS-118A, LCS-234A, LCS-210A, LCS-265A, LCS-149A, LCS-040A, LCS-169A, LCS-256A, LCS-190B, LCS-118B, LCS-234B, LCS-210B, LCS-265B, LCS-149B, LCS-040B, LCS-169B, LCS-213A, LCS-164A, LCS-223A, LCS-245A, LCS-281B, LCS-191A, LCS-171A, LCS-249A, LCS-213B, LCS-164B, LCS-245B, LCS-094B, LCS-094A, LCS-191B, LCS-171B, LCS-249B, LCS-131A, LCS-241A, LCS-074A, LCS-160A, LCS-179A, LCS-134A, LCS-224A, LCS-078A, LCS-131B, LCS-201B, LCS-074B, LCS-160B, LCS-179B, LCS-134B, LCS-147B, LCS-224B, LCS-078B, LCS-093A, LCS-253A, LCS-279A, LCS-008A, LCS-291A, LCS-281A, LCS-156A, LCS-282A, LCS-090A, LCS-151A, LCS-253B, LCS-279B, LCS-008B, LCS-172B, LCS-291B, LCS-156B, LCS-282B, LCS-090B, LCS-151B, LCS-259A, LCS-010A, LCS-264A, LCS-264B, LCS-163A, LCS-163B, LCS-089A, LCS-089B, LCS-143A, LCS-143B, LCS-199A, LCS-199B, LCS-278A, LCS-278B, LCS-119A, LCS-119B, LCS-184A, LCS-184B, LCS-203A, LCS-203B, LCS-178A, LCS-178B, LCS-284A, LCS-284B, LCS-108A, LCS-261B, LCS-043A, LCS-043B, LCS-174A, LCS-174B, LCS-166A, LCS-193A, LCS-193B, LCS-215A, LCS-215B, LCS-021A, LCS-021B, LCS-129A, LCS-129B, LCS-198A, LCS-198B, LCS-084A, LCS-084B, LCS-250A, LCS-011A, LCS-108B, LCS-011B, LCS-219A, LCS-219B, LCS-194A, LCS-194B, LCS-170A, LCS-170B, LCS-204A, LCS-204B, LCS-261A, LCS-195A, LCS-195B, LCS-200B, LCS-206A, LCS-206B, LCS-161B, LCS-145A, LCS-145B, LCS-236A, LCS-236B, LCS-270A, LCS-270B, LCS-182A, LCS-182B, LCS-197B, LCS-173B, LCS-240B, LCS-266B, LCS-167B, LCS-032B, LCS-050B, LCS-285B, LCS-031B, LCS-189A, LCS-277A, LCS-117A, LCS-267A, LCS-100A, LCS-228A, LCS-268A, LCS-222A, LCS-192A, LCS-175A, LCS-277B, LCS-117B, LCS-267B, LCS-100B, LCS-228B, LCS-268B, LCS-222B, LCS-192B, LCS-248A, LCS-121A, LCS-157A, LCS-148A, LCS-126A, LCS-260A, LCS-223B, LCS-121B, LCS-157B, LCS-148B, LCS-260B, LCS-247A, LCS-088A, LCS-243A, LCS-165A, LCS-208A, LCS-110A, LCS-146A, LCS-247B, LCS-243B, LCS-165B, LCS-208B, LCS-110B, LCS-146B, LCS-147A, LCS-173A, LCS-240A, LCS-266A, LCS-167A, LCS-032A, LCS-050A, LCS-285A, LCS-031A, LCS-106A, LCS-106B, LCS-107A, LCS-107B, LCS-109A, LCS-109B, LCS-116A, LCS-137A, LCS-137B, LCS-138A, LCS-138B, LCS-139A, LCS-139B, LCS-142A, LCS-142B, LCS-207A, LCS-231A, LCS-231B, LCS-251A, LCS-263A, LCS-263B, LCS-269A, LCS-269B, LCS-273A, LCS-273B, LCS-289A, LCS-289B, LCS-290A, LCS-290B, LCS-093B, LCS-097A, LCS-097B, LCS-104B, LCS-140B, LCS-150B, LCS-158A, LCS-161A, LCS-162B, LCS-014B, LCS-166B, LCS-172A, LCS-197A, LCS-200A, LCS-201A, LCS-216A, LCS-216B, LCS-238A, LCS-241B, LCS-046A, LCS-248B, LCS-259B, Normal1, Normal2, LCS-003B, LCS-006B, LCS-026B, LCS-128B, LCS-168B, LCS-181B, LCS-190A, X02-342A, X02-342B, X02-362A, X02-362B

			Action	DRS
	Lympho_8plex_pH6.msf	Msf
	Velos02_04799.raw	Raw
	Velos02_04800.raw	Raw
	Velos02_04801.raw	Raw
	Velos02_04802.raw	Raw