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

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-Sjogren 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.

Automated summary

Cell surface and secreted proteins are essential for multicellular life and undergo maturation and folding in the endoplasmic reticulum (ER). BiP, an ER chaperone, plays a key role in assisting unfolded client proteins. Loss of SIL1 function is a leading cause of Marinesco-Sjogren syndrome (MSS). Understanding the molecular mechanisms of SIL1's NEF activity may lead to new pharmacological approaches for treating MSS.