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 SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s 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.
Highlights
As a misfolded protein begins to emerge into the cytosol, it is ubiquitinated by integral membrane ubiquitin ligases, which allows it to be extracted from the endoplasmic reticulum (ER) by the p97 AAA+ ATPase and targeted for degradation by the cytosolic 26S proteasome
SIL1 was significantly upregulated during LPS-mediated differentiation of wild-type lymphocytes, those from Sil1Gt mice did not compensate by increasing the levels of GRP170 or other chaperones beyond that occurring as part of the differentiation schema
Since SIL1 plays a crucial role in maintaining ER homeostasis in neurons, it did not come as a complete surprise when SIL1 was implicated as a modifier in amyotrophic lateral sclerosis (ALS) [101]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The nascent polypeptide enters the endoplasmic reticulum (ER) co-translationally, where it undergoes processing and post-translational modifications, which may include cleavage of the signal sequence, N-linked glycosylation, disulfide bond formation, and assembly of subunits in the case of multimeric proteins [2]. The ER consists of two major families of molecular chaperones with broad client specificities, the heat shock protein (HSP) chaperones [3] and the glycan-binding lectin chaperones [4], both of which are complemented by a diverse set of co-chaperones These chaperone families are further assisted by ER-resident protein folding enymes, including peptidyl prolyl cis/trans isomerases, which promote isomerization of the cis and trans peptide bond between prolines and the preceeding amino acid [5,6], and more than 20 ERlocalized oxidoreductases that catalyze the formation, reduction, and/or isomerizaton of disulfide bonds between cysteines [7].
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