HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: Relevance to hematological and mitochondrial diseases.

Most iron in humans is bound in heme used as a prosthetic group for hemoglobin. Heme-regulated inhibitor (HRI) is responsible for coordinating heme availability and protein synthesis. Originally characterized in rabbit reticulocyte lysates, HRI was shown in 1976 to phosphorylate the α-subunit of eukaryotic initiation factor 2, revealing a new molecular mechanism for regulating protein synthesis. Since then, HRI research has mostly been focused on the biochemistry of heme inhibition through direct binding and heme sensing in balancing heme and globin synthesis to prevent proteotoxicity in erythroid cells. Beyond inhibiting translation of highly translated mRNAs, eukaryotic initiation factor 2α phosphorylation also selectively increases translation of certain poorly translated mRNAs, notably activating transcription factor 4 mRNA, for reprogramming of gene expression to mitigate stress, known as the integrated stress response (ISR). In recent years, there have been novel mechanistic insights of HRI-ISR in oxidative stress, mitochondrial function, and erythroid differentiation during heme deficiency. Furthermore, HRI-ISR is activated upon mitochondrial stress in several cell types, establishing the bifunctional nature of HRI protein. The role of HRI and ISR in cancer development and vulnerability is also emerging. Excitingly, the UBR4 ubiquitin ligase complex has been demonstrated to silence the HRI-ISR by degradation of activated HRI proteins, suggesting additional regulatory processes. Together, these recent advancements indicate that the HRI-ISR mechanistic axis is a target for new therapies for hematological and mitochondrial diseases as well as oncology. This review covers the historical overview of HRI biology, the biochemical mechanisms of regulating HRI, and the biological impacts of the HRI-ISR pathway in human diseases.