EurekaMag.com logo
+ Site Statistics
References:
54,215,046
Abstracts:
30,230,908
PMIDs:
28,215,208
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

Novel Mechanisms for Heme-dependent Degradation of ALAS1 Protein as a Component of Negative Feedback Regulation of Heme Biosynthesis



Novel Mechanisms for Heme-dependent Degradation of ALAS1 Protein as a Component of Negative Feedback Regulation of Heme Biosynthesis



Journal of Biological Chemistry 291(39): 20516-20529



In eukaryotic cells, heme production is tightly controlled by heme itself through negative feedback-mediated regulation of nonspecific 5-aminolevulinate synthase (ALAS1), which is a rate-limiting enzyme for heme biosynthesis. However, the mechanism driving the heme-dependent degradation of the ALAS1 protein in mitochondria is largely unknown. In the current study, we provide evidence that the mitochondrial ATP-dependent protease ClpXP, which is a heteromultimer of CLPX and CLPP, is involved in the heme-dependent degradation of ALAS1 in mitochondria. We found that ALAS1 forms a complex with ClpXP in a heme-dependent manner and that siRNA-mediated suppression of either CLPX or CLPP expression induced ALAS1 accumulation in the HepG2 human hepatic cell line. We also found that a specific heme-binding motif on ALAS1, located at the N-terminal end of the mature protein, is required for the heme-dependent formation of this protein complex. Moreover, hemin-mediated oxidative modification of ALAS1 resulted in the recruitment of LONP1, another ATP-dependent protease in the mitochondrial matrix, into the ALAS1 protein complex. Notably, the heme-binding site in the N-terminal region of the mature ALAS1 protein is also necessary for the heme-dependent oxidation of ALAS1. These results suggest that ALAS1 undergoes a conformational change following the association of heme to the heme-binding motif on this protein. This change in the structure of ALAS1 may enhance the formation of complexes between ALAS1 and ATP-dependent proteases in the mitochondria, thereby accelerating the degradation of ALAS1 protein to maintain appropriate intracellular heme levels.

(PDF emailed within 0-6 h: $19.90)

Accession: 058430362

Download citation: RISBibTeXText

PMID: 27496948

DOI: 10.1074/jbc.M116.719161



Related references

Regulation of heme metabolism in rat hepatocytes and hepatocyte cell lines: delta-aminolevulinic acid synthase and heme oxygenase are regulated by different heme-dependent mechanisms. Archives of Biochemistry and Biophysics 384(2): 280-295, 2001

Differential regulation of human ALAS1 mRNA and protein levels by heme and cobalt protoporphyrin. Molecular and Cellular Biochemistry 319(1-2): 153-161, 2008

Immuno-spin trapping of heme-induced protein radicals Implications for heme oxygenase-1 induction and heme degradation. Free Radical Biology and Medicine 61: 265-272, 2013

Immuno-spin trapping of heme-induced protein radicals: Implications for heme oxygenase-1 induction and heme degradation. Free Radical Biology & Medicine 61: 265-272, 2015

PPARa Controls Hepatic Heme Biosynthesis Through ALAS1. 2009

Heme oxygenase inhibits nitric oxide synthase by degrading heme: a negative feedback regulation mechanism for nitric oxide production. Transplantation Proceedings 30(8): 4184-4185, 1998

Regulation of heme biosynthesis in Salmonella typhimurium: activity of glutamyl-tRNA reductase (HemA) is greatly elevated during heme limitation by a mechanism which increases abundance of the protein. Journal of Bacteriology 179(9): 2907-2914, 1997

The Cytoplasmic Heme-binding Protein (PhuS) from the Heme Uptake System of Pseudomonas aeruginosa Is an Intracellular Heme-trafficking Protein to the -Regioselective Heme Oxygenase. Journal of biological chemistry12 281(19): 13652-13662, 2006

The cytoplasmic heme-binding protein (PhuS) from the heme uptake system of Pseudomonas aeruginosa is an intracellular heme-trafficking protein to the delta-regioselective heme oxygenase. Journal of Biological Chemistry 281(19): 13652-13662, 2006

Peroxisome proliferator-activated receptor alpha controls hepatic heme biosynthesis through ALAS1. Journal of Molecular Biology 388(2): 225-238, 2009

The heme oxygenase dilemma in cellular homeostasis: new insights for the feedback regulation of heme catabolism. Tohoku Journal of Experimental Medicine 200(4): 167-186, 2003

Degradation of heme in gram-negative bacteria: the product of the hemO gene of Neisseriae is a heme oxygenase. Journal of Bacteriology 182(23): 6783-6790, 2000

Heme biosynthesis and its regulation: towards understanding and improvement of heme biosynthesis in filamentous fungi. Applied Microbiology and Biotechnology 91(3): 447-460, 2012

Degradation of meso heme and hydroxy meso heme catalyzed by the heme oxygenase ec 1.14.99.3 system involvement of hydroxy heme in the sequence of heme catabolism. Journal of Biochemistry (Tokyo) 90(1): 125-132, 1981

Heme and heme biosynthesis intermediates induce heme oxygenase-1 and cytochrome P450 2A5, enzymes with putative sequential roles in heme and bilirubin metabolism: different requirement for transcription factor nuclear factor erythroid- derived 2-like 2. Toxicological Sciences 130(1): 132-144, 2013