Hepatic heme-regulated inhibitor (HRI) eukaryotic initiation factor 2alpha kinase: a protagonist of heme-mediated translational control of CYP2B enzymes and a modulator of basal endoplasmic reticulum stress tone.
We have reported previously that the hepatic heme-regulated inhibitor (HRI)-eukaryotic initiation factor 2 alpha (eIF2 alpha) kinase is activated in acute heme-deficient states, resulting in translational shut-off of global hepatic protein synthesis, including phenobarbital (PB)-mediated induction of CYP2B enzymes in rats. These findings revealed that heme regulates hepatic CYP2B synthesis at the translational level via HRI. As a proof of concept, we have now employed a genetic HRI-knockout (KO) mouse hepatocyte model. In HRI-KO hepatocytes, PB-mediated CYP2B protein induction is no longer regulated by hepatic heme availability and proceeds undeterred even after acute hepatic heme depletion. It is noteworthy that genetic ablation of HRI led to a small albeit significant elevation of basal hepatic endoplasmic reticulum (ER) stress as revealed by the activation of ER stress-inducible RNA-dependent protein kinase-like ER-integral (PERK) eIF2 alpha-kinase, and induction of hepatic protein ubiquitination and ER chaperones Grp78 and Grp94. Such ER stress was further augmented after PB-mediated hepatic protein induction. These findings suggest that HRI normally modulates the basal hepatic ER stress tone. Furthermore, because HRI exists in both human and rat liver in its heme-sensitive form and is inducible by cytochrome P450 inducers such as PB, these findings are clinically relevant to acute heme-deficient states, such as the acute hepatic porphyrias. Activation of this exquisitely sensitive heme sensor would normally protect cells by safeguarding cellular energy and nutrients during acute heme deficiency. However, similar HRI activation in genetically predisposed persons could lead to global translational arrest of physiologically relevant enzymes and proteins, resulting in the severe and often fatal clinical symptoms of the acute hepatic porphyrias.
Acharya
Poulomi
P
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Chen
Jane-Jane
JJ
Correia
Maria Almira
MA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D002478:Cells, Cultured; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006418:Heme / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D019892:eIF-2 Kinase / Q000032:analysis / Q000502:physiology*
D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D000091342:Endoplasmic Reticulum Chaperone BiP; D006418:Heme; D017346:Protein Serine-Threonine Kinases; D013250:Steroid Hydroxylases; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C025619:steroid 16-beta-hydroxylase; C529271:EIF2AK4 protein, human