A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses

• Published in: Nature structural & molecular biology Vol. 17; no. 10; pp. 1188 - 1194
• Main Authors: Sun, Dawei, Kim, Kyung-Jin, Park, Chankyu, Chung, Jongkyeong, Kim, Bo Yeon, Jeon, Young Ho, Kim, Yongsung, Lee, Jun Hee, Hong, Jong-In, Kim, Hye-Yeon, Park, Seung-Yeol, Choy, Hyon E, Rhee, Hyun-Woo, Lee, Gina, Kim, Jung Hoe
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2010; Nature Publishing Group
• Subjects: 631/208/2156; 631/80/83; 631/80/86/2369; Amino Acid Motifs; Amino Acid Sequence; Amino acids; Amino Acids - pharmacology; Animals; Bacteria; Binding Sites; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Catalytic Domain; Cellular biology; Conserved Sequence; Deoxyribonucleic acid; DNA; Drosophila melanogaster - chemistry; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - physiology; Gene Deletion; Gene Expression Regulation; Genetic Complementation Test; Guanosine Tetraphosphate - metabolism; Heat-Shock Proteins - biosynthesis; Heat-Shock Proteins - genetics; Homology (Biology); Humans; Hydrolysis; Life Sciences; Ligases - metabolism; Manganese - metabolism; Membrane Biology; Metazoa; Models, Molecular; Molecular biology; Molecular Sequence Data; Nutrients; Oligonucleotide Array Sequence Analysis; Physiological aspects; Properties; Protein Conformation; Protein hydrolysates; Protein Structure; Protein synthesis; Proteins; Pyrophosphatases - chemistry; Pyrophosphatases - deficiency; Pyrophosphatases - genetics; Pyrophosphatases - physiology; Starvation - physiopathology; Structure-Activity Relationship; South Korea
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.1906

SpoT has a key role in the bacterial starvation response. Now the metazoan ortholog of SpoT, Mesh1, has been identified, and the structure reveals a conserved active site that can catalyze ppGpp hydrolysis. The Drosophila Mesh1 deletion mutant has impaired starvation resistance, and microarray analysis gives further insight into the starvation response. In nutrient-starved bacteria, RelA and SpoT proteins have key roles in reducing cell growth and overcoming stresses. Here we identify functional SpoT orthologs in metazoa (named Mesh1, encoded by HDDC3 in human and Q9VAM9 in Drosophila melanogaster ) and reveal their structures and functions. Like the bacterial enzyme, Mesh1 proteins contain an active site for ppGpp hydrolysis and a conserved His-Asp–box motif for Mn 2+ binding. Consistent with these structural data, Mesh1 efficiently catalyzes hydrolysis of guanosine 3′,5′-diphosphate (ppGpp) both in vitro and in vivo . Mesh1 also suppresses SpoT-deficient lethality and RelA-induced delayed cell growth in bacteria. Notably, deletion of Mesh1 ( Q9VAM9 ) in Drosophila induces retarded body growth and impaired starvation resistance. Microarray analyses reveal that the amino acid–starved Mesh1 null mutant has highly downregulated DNA and protein synthesis–related genes and upregulated stress-responsible genes. These data suggest that metazoan SpoT orthologs have an evolutionarily conserved function in starvation responses.