Illustration from Scientific Research

Putative mechanism of MANF signaling through IRE1. Upon ER stress MANF and BiP levels are increasing, and when BiP dissociates from IRE1 LD or its oligomerization site to bind misfolded proteins, progressively accumulating in the ER lumen, MANF can directly bind to IRE1 LD. This binding is preventing IRE1 hyperoligomerization, decreasing IRE1 phosphorylation, and downregulating downstream targets of IRE1 LD, resulting in neuroprotective and neurorestorative effect bothin vitroandin vivo.

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