Dr Glenn Masson - University of Dundee

Event details

Abstract

Haem-Regulated Inhibitor (HRI, also known as EIF2AK1) is one of four stress-sensing mammalian kinases that phosphorylate eIF2α as part of the Integrated Stress Response (ISR). Although HRI was first characterized as a haem-sensing kinase in red blood cell progenitors, recent studies have revealed a second role: sensing mitochondrial stress via the mitochondrial protein DELE1. Under stress, DELE1 is cleaved, and its C-terminal fragment (S-DELE/DELE1CTD) is released from the mitochondria to the cytoplasm, where it binds HRI, activating it and triggering the ISR. This pathway has been shown to be critical for neuronal health, we recently published a study in collaboration with Prof Miratul Muqit which details how this pathway connects mitochondrial health to PINK1 signalling, a major target for Parkinson's disease In this talk I will discuss how the C-terminal fragment of DELE1 binds tightly to the N-terminal region of HRI directly, competing with hemin binding, pointing to a shared interaction site on HRI. Using Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS), we map the binding footprint of DELE1CTD on HRI and show that it overlaps with the haem-binding site through extensive interactions on unstructured regions of HRI. We also show how hemin and ATP-competitive drugs have distinct mechanisms of action, again using HDX-MS. Together, these findings support a simple activation mechanism: DELE1CTD activates HRI by excluding inhibitory haem from its binding site.