Monday, January 3, 2011

stringent response... in Drosophila?

If you happened to be a bacteria, you must prepare for trouble: shortage of food, temperature changes and so on. And when the trouble comes, you should respond accordingly. Stringent response system does exactly that: it integrates several input sources (aminoacid, fat and carbon limitation, temperature upshift to name a few) and alters concentration of the alarmone molecule ppGpp (GDP with 2 extra phosphates attached to the sugar moiety).

ppGpp in turn regulates everything: transcription, translation, replication. Therefore it is a must to control ppGpp levels very precisely, and to that end bacteria have proteins which produce ppGpp (RelA), (mostly)degrade it (SpoT) and do both (Rel). All together these proteins are called RelA-SpoT homologues (RSH).

All this is in bacteria... how about eukaryotes? Well, organelles have RSH, with some of them being rather peculiar in terms of signals they respond to, such as Ca++ sensitive OsCRSH1 RSH from chloroplasts. But what about cytozolic proteins?

Exactly that was discovered in 2010 - cytozolic RSH Mesh1 in drosophila. It is a small protein, capable of only ppGpp hydrolysis, which it does specifically: it takes only this nucleotide among the variety of different ones tested. Knock-out has a strong and specific phenotype, suggesting that the Mesh1 is important and functional. Moreover, Mesh1 can substitute SpoT in bacteria. X-ray structure of the protein was solved, so the paper went into Nature Structural Biology.

The big question here is how did Mech1 end up in eukaryotes and why is it retained there? How do you transfer such a complex system as stringent response from bacteria to eukaryotes?

With RSH proteins one can not just have a ppGpp-producing one - in this case you produce ppGpp, it accumulates and the bug dies. Therefore usually bugs have Rel - it both makes and degrades ppGpp, so the whole system is in one protein. Mesh1 degrades ppGpp, and no cytozolic RSH capable of synthesis were identified in eukaryotes so far... so what is Mesh1 doing? what is it degrading?

May be there is some ppGpp-producing protein which is not homologous to RSH, and this s the source of ppGpp which Mesh1 degrades. However, attempts to spot ppGpp during aminoacid deprivation were invariably unsuccessful. So it may be Mesh1 actually does something else then ppGpp hydrolysis.


Sun D, Lee G, Lee JH, Kim HY, Rhee HW, Park SY, Kim KJ, Kim Y, Kim BY, Hong JI, Park C, Choy HE, Kim JH, Jeon YH, & Chung J (2010). A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nature structural & molecular biology, 17 (10), 1188-94 PMID: 20818390

Mitkevich VA, Ermakov A, Kulikova AA, Tankov S, Shyp V, Soosaar A, Tenson T, Makarov AA, Ehrenberg M, & Hauryliuk V (2010). Thermodynamic characterization of ppGpp binding to EF-G or IF2 and of initiator tRNA binding to free IF2 in the presence of GDP, GTP, or ppGpp. Journal of molecular biology, 402 (5), 838-46 PMID: 20713063

Maciag M, Kochanowska M, Lyzeń R, Wegrzyn G, & Szalewska-Pałasz A (2010). ppGpp inhibits the activity of Escherichia coli DnaG primase. Plasmid, 63 (1), 61-7 PMID: 19945481

Gralla JD (2005). Escherichia coli ribosomal RNA transcription: regulatory roles for ppGpp, NTPs, architectural proteins and a polymerase-binding protein. Molecular microbiology, 55 (4), 973-7 PMID: 15686546

Pollard JW, Lam T, & Stanners CP (1980). Mammalian cells do not have a stringent response. Journal of cellular physiology, 105 (2), 313-25 PMID: 7462330

Buckstein MH, He J, & Rubin H (2008). Characterization of nucleotide pools as a function of physiological state in Escherichia coli. Journal of bacteriology, 190 (2), 718-26 PMID: 17965154

Mendeley group on stringent response

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