Heme regulates protein homeostasis at transcription, protein translation, and degradation levels
Received date: 15 Jul 2010
Accepted date: 06 Sep 2010
Published date: 01 Dec 2010
Copyright
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.
Key words： heme; transcription; protein translation; protein degradation
Fang YANG , En-Duo WANG . Heme regulates protein homeostasis at transcription, protein translation, and degradation levels[J]. Frontiers in Biology, 2010 , 5(6) : 516 -523 . DOI: 10.1007/s11515-010-7700-5
| 1 |
Acharya P, Chen J J, Correia M A (2010). 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.Mol Pharmacol, 77(4): 575–592
|
| 2 |
Becerra M, Lombardía-Ferreira L J, Hauser N C, Hoheisel J D, Tizon B, Cerdán M E (2002). The yeast transcriptome in aerobic and hypoxic conditions: effects of hap1, rox1, rox3 and srb10 deletions.Mol Microbiol, 43(3): 545–555
|
| 3 |
Brower C S, Varshavsky A, Hansen I A (2009). Ablation of arginylation in the mouse N-end rule pathway: loss of fat, higher metabolic rate, damaged spermatogenesis, and neurological perturbations.PLoS ONE, 4(11): e7757
|
| 4 |
Chen J J (2000). In: Soneberg N, Hershey J W B, Mathews M B, eds. Translational Control of Gene Expression. NY: Cold Spring Harbor Laboratory Press, 529–546
|
| 5 |
Chen J J (2007). Regulation of protein synthesis by the heme-regulated eIF2α kinase: relevance to anemias. Blood, 109(7): 2693–2699
|
| 6 |
Chen J J, London I M (1995). Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase.Trends Biochem Sci, 20(3): 105–108
|
| 7 |
Dever T E (2002). Gene-specific regulation by general translation factors.Cell, 108(4): 545–556
|
| 8 |
Dioum E M, Rutter J, Tuckerman J R, Gonzalez G, Gilles-Gonzalez M A, McKnight S L (2002). NPAS2: a gas-responsive transcription factor.Science, 298(5602): 2385–2387
|
| 9 |
Dohi Y, Ikura T, Hoshikawa Y, Katoh Y, Ota K, Nakanome A, Muto A, Omura S, Ohta T, Ito A, Yoshida M, Noda T, Igarashi K (2008). Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin.Nat Struct Mol Biol, 15(12): 1246–1254
|
| 10 |
Dunbar A Y, Kamada Y, Jenkins G J, Lowe E R, Billecke S S, Osawa Y (2004). Ubiquitination and degradation of neuronal nitric-oxide synthase in vitro: dimer stabilization protects the enzyme from proteolysis.Mol Pharmacol, 66(4): 964–969
|
| 11 |
Etlinger J D, Goldberg A L (1980). Control of protein degradation in reticulocytes and reticulocyte extracts by hemin.J Biol Chem, 255(10): 4563–4568
|
| 12 |
Faller M, Matsunaga M, Yin S, Loo J A, Guo F (2007). Heme is involved in microRNA processing.Nat Struct Mol Biol, 14(1): 23–29
|
| 13 |
Furuyama K, Kaneko K, Vargas P D (2007). Heme as a magnificent molecule with multiple missions: heme determines its own fate and governs cellular homeostasis.Tohoku J Exp Med, 213(1): 1–16
|
| 14 |
Gattoni M, Boffi A, Sarti P, Chiancone E (1996). Stability of the heme-globin linkage in alphabeta dimers and isolated chains of human hemoglobin. A study of the heme transfer reaction from the immobilized proteins to albumin.J Biol Chem, 271(17): 10130–10136
|
| 15 |
Guillaumond F, Dardente H, Giguère V, Cermakian N (2005). Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors.J Biol Rhythms, 20(5): 391–403
|
| 16 |
Haas A L, Rose I A (1981). Hemin inhibits ATP-dependent ubiquitin-dependent proteolysis: role of hemin in regulating ubiquitin conjugate degradation.Proc Natl Acad Sci USA, 78(11): 6845–6848
|
| 17 |
Hamza I, Chauhan S, Hassett R, O’Brian M R (1998). The bacterial irr protein is required for coordination of heme biosynthesis with iron availability.J Biol Chem, 273(34): 21669–21674
|
| 18 |
Hentze M W, Muckenthaler M U, Andrews N C (2004). Balancing acts: molecular control of mammalian iron metabolism.Cell, 117(3): 285–297
|
| 19 |
Hickman M J, Winston F (2007). Heme levels switch the function of Hap1 of Saccharomyces cerevisiae between transcriptional activator and transcriptional repressor.Mol Cell Biol, 27(21): 7414–7424
|
| 20 |
Hoffman A E, Zheng T, Ba Y, Zhu Y (2008). The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response.Mol Cancer Res, 6(9): 1461–1468
|
| 21 |
Hou S, Reynolds M F, Horrigan F T, Heinemann S H, Hoshi T (2006). Reversible binding of heme to proteins in cellular signal transduction.Acc Chem Res, 39(12): 918–924
|
| 22 |
Hu R G, Wang H, Xia Z, Varshavsky A (2008). The N-end rule pathway is a sensor of heme.Proc Natl Acad Sci USA, 105(1): 76–81
|
| 23 |
Igarashi J, Murase M, Iizuka A, Pichierri F, Martinkova M, Shimizu T (2008). Elucidation of the heme binding site of heme-regulated eukaryotic initiation factor 2alpha kinase and the role of the regulatory motif in heme sensing by spectroscopic and catalytic studies of mutant proteins.J Biol Chem, 283(27): 18782–18791
|
| 24 |
Igarashi J, Sato A, Kitagawa T, Yoshimura T, Yamauchi S, Sagami I, Shimizu T (2004). Activation of heme-regulated eukaryotic initiation factor 2alpha kinase by nitric oxide is induced by the formation of a five-coordinate NO-heme complex: optical absorption, electron spin resonance, and resonance raman spectral studies.J Biol Chem, 279(16): 15752–15762
|
| 25 |
Inuzuka T, Yun B G, Ishikawa H, Takahashi S, Hori H, Matts R L, Ishimori K, Morishima I (2004). Identification of crucial histidines for heme binding in the N-terminal domain of the heme-regulated eIF2alpha kinase.J Biol Chem, 279(8): 6778–6782
|
| 26 |
Ishikawa H, Kato M, Hori H, Ishimori K, Kirisako T, Tokunaga F, Iwai K (2005). Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2.Mol Cell, 19(2): 171–181
|
| 27 |
Kaasik K, Lee C C (2004). Reciprocal regulation of haem biosynthesis and the circadian clock in mammals.Nature, 430(6998): 467–471
|
| 28 |
Kim Y M, Son K, Hong S J, Green A, Chen J J, Tzeng E, Hierholzer C, Billiar T R (1998). Inhibition of protein synthesis by nitric oxide correlates with cytostatic activity: nitric oxide induces phosphorylation of initiation factor eIF-2 alpha.Mol Med, 4(3): 179–190
|
| 29 |
Kurosaka S, Leu N A, Zhang F, Bunte R, Saha S, Wang J, Guo C, He W, Kashina A, Bronner-Fraser M (2010). Arginylation-dependent neural crest cell migration is essential for mouse development.PLoS Genet, 6(3): e1000878
|
| 30 |
Kwon Y T, Kashina A S, Davydov I V, Hu R G, An J Y, Seo J W, Du F, Varshavsky A (2002). An essential role of N-terminal arginylation in cardiovascular development.Science, 297(5578): 96–99
|
| 31 |
Lamas S, Lowenstein C J, Michel T (2007). Nitric oxide signaling comes of age: 20 years and thriving.Cardiovasc Res, 75(2): 207–209
|
| 32 |
Lan C, Lee H C, Tang S, Zhang L (2004). A novel mode of chaperone action: heme activation of Hap1 by enhanced association of Hsp90 with the repressed Hsp70-Hap1 complex.J Biol Chem, 279(26): 27607–27612
|
| 33 |
Lee K S, Raymond L D, Schoen B, Raymond G J, Kett L, Moore R A, Johnson L M, Taubner L, Speare J O, Onwubiko H A, Baron G S, Caughey W S, Caughey B (2007). Hemin interactions and alterations of the subcellular localization of prion protein.J Biol Chem, 282(50): 36525–36533
|
| 34 |
Leu N A, Kurosaka S, Kashina A, Bergmann A (2009). Conditional Tek promoter-driven deletion of arginyltransferase in the germ line causes defects in gametogenesis and early embryonic lethality in mice.PLoS ONE, 4(11): e7734PMID:19890395
|
| 35 |
Levicán G, Katz A, de Armas M, Núñez H, Orellana O (2007). Regulation of a glutamyl-tRNA synthetase by the heme status.Proc Natl Acad Sci USA, 104(9): 3135–3140PMID:17360620
|
| 36 |
Liao M, Pabarcus M K, Wang Y, Hefner C, Maltby D A, Medzihradszky K F, Salas-Castillo S P, Yan J, Maher J J, Correia M A (2007). Impaired dexamethasone-mediated induction of tryptophan 2,3-dioxygenase in heme-deficient rat hepatocytes: translational control by a hepatic eIF2alpha kinase, the heme-regulated inhibitor.J Pharmacol Exp Ther, 323(3): 979–989
|
| 37 |
Lim E J, Joung Y H, Jung S M, Park S H, Park J H, Kim S Y, Hwang T S, Hong D Y, Chung S C, Ye S K, Moon E S, Park E U, Park T, Chung I M, Yang Y M (2010). Hemin inhibits cyclin D1 and IGF-1 expression via STAT5b under hypoxia in ERalpha-negative MDA-MB 231 breast cancer cells.Int J Oncol, 36(5): 1243–1251
|
| 38 |
Mense S M, Zhang L (2006). Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases.Cell Res, 16(8): 681–692
|
| 39 |
Meyron-Holtz E G, Ghosh M C, Rouault T A (2004). Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo.Science, 306(5704): 2087–2090
|
| 40 |
Monson E K, Weinstein M, Ditta G S, Helinski D R (1992). The FixL protein of Rhizobium meliloti can be separated into a heme-binding oxygen-sensing domain and a functional C-terminal kinase domain.Proc Natl Acad Sci USA, 89(10): 4280–4284
|
| 41 |
Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, Hayashi N, Yamamoto M, Shibahara S, Fujita H, Igarashi K (2001). Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1.EMBO J, 20(11): 2835–2843
|
| 42 |
Oglesby-Sherrouse A G, Vasil M L, Rénia L (2010). Characterization of a heme-regulated non-coding RNA encoded by the prrF locus of Pseudomonas aeruginosa.PLoS ONE, 5(4): e9930
|
| 43 |
Qi Z, Hamza I, O’Brian M R (1999). Heme is an effector molecule for iron-dependent degradation of the bacterial iron response regulator (Irr) protein.Proc Natl Acad Sci USA, 96(23): 13056–13061
|
| 44 |
Rafie-Kolpin M, Chefalo P J, Hussain Z, Hahn J, Uma S, Matts R L, Chen J J (2000). Two heme-binding domains of heme-regulated eukaryotic initiation factor-2alpha kinase. N terminus and kinase insertion.J Biol Chem, 275(7): 5171–5178
|
| 45 |
Raghuram S, Stayrook K R, Huang P, Rogers P M, Nosie A K, McClure D B, Burris L L, Khorasanizadeh S, Burris T P, Rastinejad F (2007). Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta.Nat Struct Mol Biol, 14(12): 1207–1213
|
| 46 |
Reichard J F, Sartor M A, Puga A (2008). BACH1 is a specific repressor of HMOX1 that is inactivated by arsenite.J Biol Chem, 283(33): 22363–22370
|
| 47 |
Ripperger J A (2006). Mapping of binding regions for the circadian regulators BMAL1 and CLOCK within the mouse Rev-erbalpha gene.Chronobiol Int, 23(1-2): 135–142
|
| 48 |
Salahudeen A A, Thompson J W, Ruiz J C, Ma H W, Kinch L N, Li Q, Grishin N V, Bruick R K (2009). An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis.Science, 326(5953): 722–726
|
| 49 |
Severance S, Hamza I (2009). Trafficking of heme and porphyrins in metazoa.Chem Rev, 109(10): 4596–4616
|
| 50 |
Severance S, Rajagopal A, Rao A U, Cerqueira G C, Mitreva M, El-Sayed N M, Krause M, Hamza I, Chisholm A D (2010). Genome-wide analysis reveals novel genes essential for heme homeostasis in Caenorhabditis elegans.PLoS Genet, 6(7): e1001044
|
| 51 |
Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, Tashiro S, Takahashi S, Shibahara S, Alam J, Taketo M M, Yamamoto M, Igarashi K (2002). Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene.EMBO J, 21(19): 5216–5224
|
| 52 |
Suzuki H, Tashiro S, Hira S, Sun J, Yamazaki C, Zenke Y, Ikeda-Saito M, Yoshida M, Igarashi K (2004). Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1.EMBO J, 23(13): 2544–2553
|
| 53 |
Tsai A (1994). How does NO activate hemeproteins?FEBS Lett, 341(2-3): 141–145
|
| 54 |
Uma S, Yun B G, Matts R L (2001). The heme-regulated eukaryotic initiation factor 2alpha kinase. A potential regulatory target for control of protein synthesis by diffusible gases.J Biol Chem, 276(18): 14875–14883
|
| 55 |
Varshavsky A (1996). The N-end rule: functions, mysteries, uses.Proc Natl Acad Sci USA, 93(22): 12142–12149
|
| 56 |
Vierstra R D, Sullivan M L (1988). Hemin inhibits ubiquitin-dependent proteolysis in both a higher plant and yeast.Biochemistry, 27(9): 3290–3295
|
| 57 |
Wakasugi K (2007). Human tryptophanyl-tRNA synthetase binds with heme to enhance its aminoacylation activity.Biochemistry, 46(40): 11291–11298
|
| 58 |
Wehner K A, Schütz S, Sarnow P (2010). OGFOD1, a novel modulator of eukaryotic translation initiation factor 2alpha phosphorylation and the cellular response to stress.Mol Cell Biol, 30(8): 2006–2016
|
| 59 |
Wu N, Yin L, Hanniman E A, Joshi S, Lazar M A (2009). Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.Genes Dev, 23(18): 2201–2209
|
| 60a |
Yang F, Xia X, Lei H Y, Wang E D (2010). Hemin binds to human cytoplasmic arginyl-tRNA synthetase and inhibits its catalytic activity.J Biol Chem, doi: 10.1074/jbc.M110.159913 (in press)
|
| 60 |
Yang J, Ishimori K, O’Brian M R (2005). Two heme binding sites are involved in the regulated degradation of the bacterial iron response regulator (Irr) protein.J Biol Chem, 280(9): 7671–7676
|
| 61 |
Yang J, Kim K D, Lucas A, Drahos K E, Santos C S, Mury S P, Capelluto D G, Finkielstein C V (2008). A novel heme-regulatory motif mediates heme-dependent degradation of the circadian factor period 2.Mol Cell Biol, 28(15): 4697–4711
|
| 62 |
Yang J, Panek H R, O’Brian M R (2006). Oxidative stress promotes degradation of the Irr protein to regulate haem biosynthesis in Bradyrhizobium japonicum.Mol Microbiol, 60(1): 209–218
|
| 63 |
Yin L, Wu N, Curtin J C, Qatanani M, Szwergold N R, Reid R A, Waitt G M, Parks D J, Pearce K H, Wisely G B, Lazar M A (2007). Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways.Science, 318(5857): 1786–1789
|
| 64 |
Yin L, Wu N, Lazar M A (2010). Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal, 8: e001
|
| 65 |
Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, Asahara T, Tokunaga F, Iwai K, Igarashi K (2007). Heme induces ubiquitination and degradation of the transcription factor Bach1.Mol Cell Biol, 27(19): 6962–6971
|
| 66 |
Zhang L, Guarente L (1995). Heme binds to a short sequence that serves a regulatory function in diverse proteins.EMBO J, 14(2): 313–320
|
| 67 |
Zhang L, Hach A (1999). Molecular mechanism of heme signaling in yeast: the transcriptional activator Hap1 serves as the key mediator.Cell Mol Life Sci, 56(5-6): 415–426
|
/
| 〈 |
|
〉 |