LAUSR

Secretory and cell membrane proteins are synthesized in the endoplasmic reticulum (ER), where a network of molecular chaperones and folding factors ensure correct protein folding and export to post‐ER compartments. Failure of this process leads to accumulation of unfolded/misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), a complex signalling pathway aimed at restoring ER homeostasis, whose failure eventually leads to cell death. Suppressor of Ire1/Lhs1 double mutant (SIL1) is a nucleotide exchange factor for immunoglobulin binding protein, the main ER chaperone and primary sensor of ER stress. Loss of SIL1 function causes Marinesco‐Sjögren syndrome (MSS), a rare multisystem disease of early infancy for which there is no cure. This review, examines the current understanding of SIL1 activities in the ER, and reviews experimental data describing the consequences of SIL1 deficiency in cell and animal models. We discuss the evidence supporting a role of the UPR – particularly the protein kinase RNA‐like endoplasmic reticulum kinase branch – in the pathogenesis of MSS, and how this may be pharmacologically manipulated for treatment.