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Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

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Role of the HSP70 Co-Chaperone SIL1 in Health and Disease International Journal of Molecular Sciences Review Role of the HSP70 Co-Chaperone SIL1 in Health and Disease Viraj P. Ichhaporia † and Linda M. Hendershot * Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; [email protected] * Correspondence: [email protected] † Present address: Department of Immunology, EMD Serono Research and Development Institute, Billerica, MA 01821, USA. Abstract: Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL10s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL10s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL10s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS. Keywords: endoplasmic reticulum; HSP70 chaperones; SIL1; BiP/GRP78/HSPA5; unfolded protein Citation: Ichhaporia, V.P.; Hendershot, L.M. Role of the HSP70 response; Marinesco-Sjögren syndrome; neurodegeneration; skeletal muscles; metabolism; glioma; Co-Chaperone SIL1 in Health and chemical chaperones; gene therapy Disease. Int. J. Mol. Sci. 2021, 22, 1564. https:/doi.org/10.3390/ijms 22041564 1. Introduction Academic Editor: Hideaki Itoh Nearly a third of human genomic open reading frames encode proteins that are Received: 14 January 2021 residents of single-membrane-bound organelles, the plasma membrane, or the extracellular Accepted: 30 January 2021 space [1]. The nascent polypeptide enters the endoplasmic reticulum (ER) co-translationally, Published: 4 February 2021 where it undergoes processing and post-translational modifications, which may include cleavage of the signal sequence, N-linked glycosylation, disulfide bond formation, and Publisher’s Note: MDPI stays neutral assembly of subunits in the case of multimeric proteins [2]. These manipulations occur with regard to jurisdictional claims in as the protein begins to fold into its native structure and can guide the success of the published maps and institutional affil- protein-folding process. A dedicated ER protein quality control system (ERQC) ensures iations. the fidelity of protein maturation (Figure1). It is equipped with multiple molecular chaperones and folding factors that serve to shelter the nascent polypeptide chain entering the ER and prevent its misfolding while promoting efficient maturation to the native state. The ER consists of two major families of molecular chaperones with broad client Copyright: © 2021 by the authors. specificities, the heat shock protein (HSP) chaperones [3] and the glycan-binding lectin Licensee MDPI, Basel, Switzerland. chaperones [4], both of which are complemented by a diverse set of co-chaperones. These This article is an open access article chaperone families are further assisted by ER-resident protein folding enymes, including distributed under the terms and peptidyl prolyl cis/trans isomerases, which promote isomerization of the cis and trans conditions of the Creative Commons peptide bond between prolines and the preceeding amino acid [5,6], and more than 20 ER- Attribution (CC BY) license (https:// localized oxidoreductases that catalyze the formation, reduction, and/or isomerizaton of creativecommons.org/licenses/by/ 4.0/). disulfide bonds between cysteines [7]. Through their interaction with these chaperone Int. J. Mol. Sci. 2021, 22, 1564. https://doi.org/10.3390/ijms22041564 https://www.mdpi.com/journal/ijms Int. J. J. Mol. Sci. Sci. 20212021,, 2222,, x 1564 FOR PEER REVIEW 2 of 23 unfoldedsystems, unfoldedand misfolded and misfoldedproteins are proteins also prevented are also from prevented being transported from being transportedthrough the secretorythrough the pathway, secretory thus pathway, ensuring thus that ensuring only na thattive only proteins native will proteins reach will their reach final their destina- final tiondestination [8]. [8]. Figure 1. Maintaining endoplasmic reticulum (ER) homeostasis and the ATPase cycle of BiP. Nascent secretory pathway proteins enterenter thethe ERER in in an an unfolded unfolded state state and and immediately immediately encounter encounter the the ER-resident ER-resident molecular molecu chaperones,lar chaperones, such such as the as heat the heat shock protein chaperones, BiP, GRP94, and GRP170, as well as the lectin chaperones, Calnexin and Calreticulin. Both shock protein chaperones, BiP, GRP94, and GRP170, as well as the lectin chaperones, Calnexin and Calreticulin. Both of these of these chaperone families and their associated machineries together ensure that the nascent proteins fold correctly, upon chaperone families and their associated machineries together ensure that the nascent proteins fold correctly, upon which which they can continue their journey along the secretory pathway to their final destination. However, proteins can fail theyto mature can continue properly. their These journey aberrant along proteins the secretory are recognized pathway to by their the finalsame destination. molecular chaperones However, proteins and retrotranslocated can fail to mature to properly.the cytosol These for degradation aberrant proteins by the are 26S recognized proteasome by thein a same process molecular called ER-associated chaperones and degradation retrotranslocated (ERAD). to Aberrantly the cytosol forfolded degradation proteins can by the also 26S be proteasomecleared by the in aautophagy–lysosomal process called ER-associated system. degradation (Inset) BiP depends (ERAD). on Aberrantly ATP-induced folded conforma- proteins cantional also changes be cleared to participate by the autophagy–lysosomal in multiple ER functions. system. BiP’ (Inset)s ATPase BiP cycle depends is regulated on ATP-induced by two families conformational of co-chaperones, changes toER-localized participate DnaJ-like in multiple proteins ER functions. (ERdjs) and BiP’s nucleotide ATPase cycle exchan is regulatedge factors by (NEFs). two families ERdjs enable of co-chaperones, BiP to associate ER-localized with its DnaJ-likeclient proteins proteins stably. (ERdjs) However, and nucleotide proteins must exchange be released factors from (NEFs). BiP in ERdjs order enable to fold, BiP a process to associate mediated with itsby clientNEFs, proteins such as stably.SIL1 and However, GRP170. proteinsThe released must clients be released can then from fold, BiP undergo in order protein to fold, maturation a process mediated, and traverse by NEFs, the secretory such as pathway. SIL1 and Created with BioRender.com. GRP170. The released clients can then fold, undergo protein maturation, and traverse the secretory pathway. Created with BioRender.com. In spite of the vast cellular resources dedicated to protein folding, a fraction of nas- cent polypeptidesIn spite of the fails vast to cellular attain resources their native dedicated structure. to proteinMore than folding, 100 protein-folding a fraction of nascent dis- easespolypeptides have been fails identified, to attain theirwhich native result structure. from mutations More than in individual 100 protein-folding proteins that diseases dis- rupthave their been ability identified, to reach which a native result state from in the mutations ER, and in much individual less frequently, proteins mutations that disrupt in thetheir ERQC ability apparatus to reach itself a native [9]. stateThe resulting in the ER, ab anderrantly much folded less frequently, proteins must mutations be identified in the andERQC degraded apparatus by the itself cell [9 ].through The resulting either th aberrantlye ubiquitin–proteasomal folded proteins system must be(UPS) identified or the autophagy–lysosomaland degraded by the cellmachinery through (Figure either the1) [10]. ubiquitin–proteasomal In the ER, terminally system misfolded (UPS) and or un- the assembledautophagy–lysosomal subunits of machinerymultimeric (Figurecomplexes1)[ 10are]. recognized In the ER, terminallyby some of misfolded the same andER chaperonesunassembled and subunits components of multimeric of the ERQC complexes machinery are recognized [11]. The chaperones by some of maintain the same the ER solubilitychaperones of and misfolded components proteins of the for ERQC transfer machinery through [11 the]. Theretrotranslocon, chaperones maintain a protein-con- the sol- ductingubility of channel misfolded in the proteins ER membrane. for transfer As through a misfolded the retrotranslocon, protein begins a protein-conductingto emerge into the cytosol, it is ubiquitinated by integral membrane ubiquitin ligases, which allows it to be Int. J. Mol. Sci. 2021, 22, 1564 3 of 23 channel
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