IngentaConnect Anthrax lethal factor cleaves the N-terminus of MAPKKS and induce...

Authors: Vitale, G.¹; Pellizzari, R.¹; Recchi, C.¹; Napolitani, G.¹; Mock, M.²; Montecucco, C.¹

Source: Journal of Applied Microbiology, Volume 87, Number 2, August 1999 , pp. 288-288(1)

Abstract:

The lethal toxin (LeTx) of Bacillus anthracis is the major virulence factor responsible for the death of infected animals and for cytolysis of cultured macrophages. Its catalytic component, LF, contains the characteristic zinc-binding motif of metalloproteases, it binds zinc and indirect evidence suggests that this hydrolytic activity is essential for LeTx cytotoxicity ( Limpel et al. 1994 ; Kochi et al. 1994 ). To identify substrates of LF, we have used the yeast two-hybrid system, employing an LF inactive mutant as bait. This approach has led to the identification of the MAP kinase kinases (MAPKKs) Mek1 and Mek2 as proteins capable of specific interaction with LF. LF cleaves Mek1 and Mek2 within their N-terminus in vitro and in vivo, hydrolysing a Pro8-Ile9 and a Pro10-Arg11 peptide bond in Mek1 and Mek2, respectively ( Vitale et al. 1998 ), similarly to that found with a different approach by Duesbery et al. (1998) . The removal of the amino terminus of MAPKKs eliminates the `docking site' involved in the specific interaction with MAPKs and interferes with the phospho-activation of the MAPKs ERK1 and ERK2, which become phosphorylated in cultured macrophages following toxin challenge. We are currently investigating the relevance of MAPKKs cleavage for LeTx cytotoxicity and the consequences for the activity of the MAP pathway.

Document Type: Research article

DOI: 10.1046/j.1365-2672.1999.00893.x

Affiliations: 1: Centro CNR Biomembrane and Dipartimento di Scienze Biomediche, Università di Padova, Padova, Italy and 2: Laboratoire de Génétique Moléculaire des toxines (URA 1858, CNRS), Institut Pasteur, Paris, France

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Anthrax lethal factor cleaves the N-terminus of MAPKKS and induces tyrosine/threonine phosphorylation of MAPKS in cultured macrophages