Nlec, a type III secretion protease, compromises NF-kB activation by targeting p65/rela

Hilo Yen, Tadasuke Ooka, Atsushi Iguchi, Tetsuya Hayashi, Nakaba Sugimoto, Toru Tobe

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

The NF-kB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-kB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-kB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-kB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other antiinflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-kB activation by the direct cleavage of NF-kB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-kB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.

Original languageEnglish
Article numbere1001231
JournalPLoS pathogens
Volume6
Issue number12
DOIs
Publication statusPublished - Dec 1 2010
Externally publishedYes

Fingerprint

pitrilysin
NF-kappa B
Enterohemorrhagic Escherichia coli
Enteropathogenic Escherichia coli
Zinc
Peptide Hydrolases
Anti-Inflammatory Agents
Bacteria
Foodborne Diseases
Toll-Like Receptors
Adaptive Immunity
Virulence Factors
Innate Immunity
Needles

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Nlec, a type III secretion protease, compromises NF-kB activation by targeting p65/rela. / Yen, Hilo; Ooka, Tadasuke; Iguchi, Atsushi; Hayashi, Tetsuya; Sugimoto, Nakaba; Tobe, Toru.

In: PLoS pathogens, Vol. 6, No. 12, e1001231, 01.12.2010.

Research output: Contribution to journalArticle

Yen, Hilo ; Ooka, Tadasuke ; Iguchi, Atsushi ; Hayashi, Tetsuya ; Sugimoto, Nakaba ; Tobe, Toru. / Nlec, a type III secretion protease, compromises NF-kB activation by targeting p65/rela. In: PLoS pathogens. 2010 ; Vol. 6, No. 12.
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