Open AccessALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria
Author(s) -
Milica Milivojevic,
AnneSophie Dangeard,
Christoph Kasper,
Therese Tschon,
Mario Emmenlauer,
Claudine Pique,
Pamela Schnupf,
Julie Guignot,
Cécile Arrieumerlou
Publication year - 2017
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006224
Subject(s) - biology , shigella flexneri , innate immune system , secretion , microbiology and biotechnology , immunity , inflammation , immunology , immune system , escherichia coli , gene , biochemistry
During infection by invasive bacteria, epithelial cells contribute to innate immunity via the local secretion of inflammatory cytokines. These are directly produced by infected cells or by uninfected bystanders via connexin-dependent cell-cell communication. However, the cellular pathways underlying this process remain largely unknown. Here we perform a genome-wide RNA interference screen and identify TIFA and TRAF6 as central players of Shigella flexneri and Salmonella typhimurium -induced interleukin-8 expression. We show that threonine 9 and the forkhead-associated domain of TIFA are necessary for the oligomerization of TIFA in both infected and bystander cells. Subsequently, this process triggers TRAF6 oligomerization and NF-κB activation. We demonstrate that TIFA/TRAF6-dependent cytokine expression is induced by the bacterial metabolite heptose-1,7-bisphosphate (HBP). In addition, we identify alpha-kinase 1 (ALPK1) as the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to infection with S . flexneri and S . typhimurium but also to Neisseria meningitidis . Altogether, these results clearly show that ALPK1 is a master regulator of innate immunity against both invasive and extracellular gram-negative bacteria.