Heme regulates protein homeostasis at transcription, protein translation, and degradation levels

doi:10.1007/s11515-010-7700-5

Front Biol

2010, Vol. 5

Issue (6) : 516-523 https://doi.org/10.1007/s11515-010-7700-5

REVIEW

Heme regulates protein homeostasis at transcription, protein translation, and degradation levels

Fang YANG, En-Duo WANG(

)

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

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Abstract

Heme, as a prosthetic group of proteins, is an iron-protoporphyrin involved in a wide range of cellular functions. Cellular heme levels vary due to the accurate balance of its synthesis and degradation. The “heme sensor protein” is currently a focus of investigation because heme has been found as a cellular signaling messenger involved in various biologic processes, including gene expression, protein localization, protein stability and microRNA processing. Several eukaryotic transcriptional factors can be regulated by heme, including heme activator protein (Hap1), Bach1, REV-erbα, and neuronal PAS domain protein 2 (NPAS2). Especially, the two circadian transcriptional factors serving as the heme sensor, REV-erbα and NPAS2, coordinate the circadian clock with metabolic pathways. It is well established that heme regulates the activity of heme-regulated eukaryotic initiation factor 2α (eIF2α) kinase (HRI), which serves as a feedback inhibitor of protein translation in both erythroid and non- erythroid cells. Additionally, heme is involved in protein degradation by inducing the degradation of several proteins such as the iron response regulator (Irr), iron regulatory protein 2 (IRP2), Bach1, and circadian factor period 2 (Per2). The N-end rule ubiquitin-dependent protein degradation pathway has also been identified as a sensor of heme, which blocks the function of arginyl-tRNA protein transferase (ATE1) and E3 ubiquitin ligase. In this review, we summarize the regulatory roles of heme at the levels of transcription, protein translation, and protein degradation, highlighting the role of heme in maintaining cellular homeostasis.

Keywords heme transcription protein translation protein degradation

Corresponding Author(s): WANG En-Duo,Email:edwang@sibs.ac.cn

Issue Date: 01 December 2010

Cite this article:

En-Duo WANG,Fang YANG. Heme regulates protein homeostasis at transcription, protein translation, and degradation levels[J]. Front Biol, 2010, 5(6): 516-523.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-010-7700-5
https://academic.hep.com.cn/fib/EN/Y2010/V5/I6/516

Fig.1 Heme regulates gene transcription by binding to Rev-erbα. Heme-bound Rev-erbα can recruit corepressor NcoR-HDAC3 complex and then suppress the transcription of target genes, including Bmal1, PGC1-α and metabolic genes. PGC1-α: PPARγ coactivator-1 α.

Fig.2 Heme regulates protein translation by binding to HRI: two heme- binding site model. HRI monomer is synthesized with one heme molecule binding to the N-terminal domain stably. In heme deficiency, the kinase is activated by autophosphorylation. The active HRI phosphorylates eIF2α at Ser-51 and results in decreased protein translation. Under heme-abundant conditions, heme binds to the other binding site in kinase insertion domain and inhibits the kinase activity of HRI, allowing protein translation going on. HRI: heme-regulated eukaryotic initiation factor 2α (eIF2α) kinase.

Fig.3 A portion of N-end rule pathway. Hemin blocks the function of ATE1 and E3 ubiquitin ligase. ATE1: Arginyl-tRNA protein transferase; ArgRS: arginyl-tRNA synthetase.

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