期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2110877119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Many effectors of the
Coxiella burnetii Dot/Icm transporter are important for its virulence, but the lack of understanding of their biochemical activity prevents the use of them as potential therapeutic targets. Here, we found that the effector Cbu0513 (CinF) is a protein phosphatase that attacks IκBα, a key regulatory protein in NF-κB signaling. Unlike its homologs such as ST0318 from the archaeon
Sulfolobus tokodaii, CinF has lost the enzymatic activity as a fructose-1,6-bisphosphate aldolase/phosphatase. Instead, it specifically targets IκBα to make it resistant to proteasome-mediated degradation in cells stimulated with NF-κB agonists. Our finding has expanded the strategy used by bacterial pathogens to inhibit host immunity, which may provide leads for the development of immune modulators for disease treatment.
Coxiella burnetii is a bacterial pathogen that replicates within host cells by establishing a membrane-bound niche called the
Coxiella-containing vacuole. Biogenesis of this compartment requires effectors of its Dot/Icm type IV secretion system. A large cohort of such effectors has been identified, but the function of most of them remain elusive. Here, by a cell-based functional screening, we identified the effector Cbu0513 (designated as CinF) as an inhibitor of NF-κB signaling. CinF is highly similar to a fructose-1,6-bisphosphate (FBP) aldolase/phosphatase present in diverse bacteria. Further study reveals that unlike its ortholog from
Sulfolobus tokodaii, CinF does not exhibit FBP phosphatase activity. Instead, it functions as a protein phosphatase that specifically dephosphorylates and stabilizes IκBα. The IκBα phosphatase activity is essential for the role of CinF in
C. burnetii virulence. Our results establish that
C. burnetii utilizes a protein adapted from sugar metabolism to subvert host immunity.
关键词：enNF-κBprotein phosphatasetype IV secretioneffectors
