[OT] Pathogens Use Previously Undescribed Mechanism To Sabotage Host Immune System

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Pathogens Use Previously Undescribed Mechanism To Sabotage Host Immune System

10 Dec 2007

New research identifies a previously unknown enzymatic mechanism that subverts

the early host immune response and promotes pathogenicity by manipulating a

common signaling pathway in host cells. The research, published by Cell Press in

the December 14th issue of Molecular Cell, may have important implications for

the food industry and for development of new antibiotics. In addition, the

results lead to intriguing questions about whether mammalian cells can make use

of a similar mechanism for potentially permanent and irreversible

posttranslational modifications.

Many gram-negative bacterial pathogens have evolved specialized mechanisms for

disrupting the ability of host cells to activate innate immune responses that

will provide immediate defense against infection. Mitogen-activated protein

kinase (MAPK) pathways play key roles in activating host innate immune responses

and are frequent targets of pathogenic effectors in both plants and animal

systems. All MAPKs contain a threonine -X-tyrosine motif and require

phosphorylation of both threonine and tyrosine for activation. Previous work

demonstrated that members of the OspF family, including OspF from Shigella and

SpvC from Salmonella, are phosphothreonine lyases that promote pathogenicity by

directly targeting and irreversibly inhibiting the activation of MAPKs.

Dr. Feng Shao from the National Institute of Biological Sciences, Beijing and

colleagues used mass spectrometry to examine the mechanism underlying

inactivation of MAPKs by the OspF family of effectors. The researchers

determined the crystal structure of SpvC and its complex with a phosphopeptide

substrate. The enzyme-substrate complex revealed how SpvC docks with activated

MAPK by recognizing the phosphotyrosine and then maneuvers the phosphothreonine

into the enzyme active site. These data implicated the MAPK p38 as the likely

preferred substrate for OspF and SpvC during bacterial infection because it has

the required conformational flexibility for this interaction. The researchers

went on to identify a previously unknown catalytic mechanism of acid-base

mediated " -elimination of phosphoserine/phosphothreonine that irreversibly

inactivated the kinase.

" Our data provide biochemical and structural evidence for specific recognition

of the dual phosphorylated MAPK substrates by the OspF family of

phosphothreonine lyases and explain the enzyme's differential activities towards

different MAPK substrates, " explains Dr. Shao. Further, as phosphorylation of

serine and threonine residues is widely used as a regulatory mechanism in

mammalian cells, the researchers speculated that phosphoserine or

phosphothreonine lyases might exist in eukaryotes and serve as

post-translational modification enzymes that irreversible dephosphorylate

kinases or other phosphorylated substrates.

Article adapted by Medical News Today from original press release.

The researchers include Yongqun Zhu, National Institute of Biological Sciences,

Beijing, China, and National Laboratory of Macromolecules, Institute of

Biophysics, Chinese Academy of Sciences, Beijing, China; Hongtao Li,National

Institute of Biological Sciences, Beijing, China; Chengzu Long, National

Institute of Biological Sciences, Beijing, China; Liyan Hu,National Institute of

Biological Sciences, Beijing, China; Hao Xu,National Institute of Biological

Sciences, Beijing, China; Liping Liu, National Institute of Biological Sciences,

Beijing, China; She Chen, National Institute of Biological Sciences, Beijing,

China; Da-Cheng Wang, National Laboratory of Macromolecules, Institute of

Biophysics, Chinese Academy of Sciences, Beijing, China; and Feng Shao, National

Institute of Biological Sciences, Beijing, China.

Source: Cathleen Genova

Cell Press

Article URL: http://www.medicalnewstoday.com/articles/91178.php