The ER stress transcription factor Luman/CREB3 is a novel regulator of Schwann cell survival and myelinating capacity through the activation of the unfolded protein response and cholesterol biosynthesis pathways

Abstract

Misfolded protein accumulation in demyelinating disorders or injury can trigger internal endoplasmic reticulum (ER) stress alleviation mechanisms, namely the unfolded protein response (UPR) and cholesterol biosynthesis pathways. Here we demonstrate that the ER stress-associated transcription factor Luman/CREB3, herein called Luman, shown to drive axon regeneration by UPR-dependent regulation of adaptive low-level stress, also positively regulates rat Schwann cell (SC) survival, myelination, the UPR, and cholesterol production in vitro. siRNA knockdown of SC Luman expression decreased SC viability and increased apoptosis 48 hours post-transfection. Dorsal root ganglion (DRG) neuron/SC co-cultures where SCs overexpressed Luman exhibited increased myelination. Simulation of unstressed, mild and moderate ER stress by tunicamycin-mediated UPR induction in SCs, allowed examination of Luman on expression of known UPR regulators, including Xbp1, Xbp1s, CHOP, and pIRE1. They collectively demonstrate a cytoprotective role for Luman under manageable ER stress. Total cholesterol levels and sterol precursor Srebf1 expression, key to myelination, also decreased following Luman knockdown. Finally, levels of mature brain-derived neurotrophic factor (mBDNF), a positive regulator of myelination and also regulated by the UPR, decreased with Luman knockdown. In contrast, pro-apoptotic BDNF precursor (proBDNF) levels increased in Luman-deficient SCs at higher ER stress levels, indicating that any protection Luman confers at moderate ER stress levels is lost upon its reduced expression. In conclusion, a connection between Luman and adaptive beneficial ER stress pathways linked to survival and myelination capacity in SCs exists. These Luman-driven cytoprotective mechanisms including survival and myelination open avenues for targeting this pathway in nerve trauma and myelinating disorders.