title: Tracking Effects of SIL1 Increase: Taking a Closer Look Beyond the Consequences of Elevated Expression Level.
abstract: 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 the 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's disease. Here, we addressed these controversial findings. Applying cell biological, morphological and biochemical methods, we demonstrated that SIL1 increases in various mammalian cells and neuronal tissues upon cellular stress. Investigation of heterozygous 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 agrees with the described adverse SIL1 effect. However, our results also suggest that protective levels are achieved by the secretion of excessive SIL1 and GRP170 and that moderately increased SIL1 also ameliorates cellular fitness under stress conditions. Our immunoprecipitation results indicate that SIL1 might act in a BiP-independent manner. Proteomic studies showed that SIL1 elevation alters the expression of proteins including crucial players in neurodegeneration, especially in Alzheimer's disease. This finding agrees with our observation of increased SIL1 immunoreactivity in surviving neurons of Alzheimer's disease autopsy cases and supports the assumption that SIL1 plays a protective role in neurodegenerative disorders.
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Labisch
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Buchkremer
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Otto-Hahn-Str. 6b, 44227, Dortmund, Germany.
authors.forename: Vietxuan
authors.initials: V
authors.lastname: Phan
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Otto-Hahn-Str. 6b, 44227, Dortmund, Germany.
authors.forename: Laxmikanth
authors.initials: L
authors.lastname: Kollipara
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gatz
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Lentz
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Nolte
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Vervoorts
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: José Andrés González
authors.initials: JAG
authors.lastname: Coraspe
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Otto-Hahn-Str. 6b, 44227, Dortmund, Germany.|Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.|Medizinisches Proteom-Center (MPC), Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Sickmann
authors.affiliation: Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, International Centre for Life, Central Parkway, Newcastle upon Tyne, England, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Carr
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Otto-Hahn-Str. 6b, 44227, Dortmund, Germany.
authors.forename: René P
authors.initials: RP
authors.lastname: Zahedi
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany. andreas.roos@isas.de.|Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Otto-Hahn-Str. 6b, 44227, Dortmund, Germany. andreas.roos@isas.de.|Institute of Genetic Medicine, John Walton Muscular Dystrophy Research Centre, International Centre for Life, Central Parkway, Newcastle upon Tyne, England, UK. andreas.roos@isas.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
mesh_terms: D000818:Animals; D058948:Cell Tracking / Q000379:methods; D002478:Cells, Cultured; D054022:Cerebrum / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D040901:Proteomics / Q000379:methods
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C000594797:SIL1 protein, mouse
keywords: BiP/GRP78; Chaperonopathy; Co-chaperone; HYOU1/GRP170; Marinesco-Sjögren syndrome; Neuroprotection