Human NLRC4 can act as a direct sensor for cytosolic flagellin
- 1Department of Innate Immunity, Institute of Immunology, University of Tuebingen, Tuebingen, Germany
Abstract
Innate immune cells sense pathogenic bacteria like Legionella pneumophila through patterns such as the protein flagellin, a critical component of the bacterial motility apparatus. Recognition of cytosolic flagellin in mouse immune cells is well understood and mediated by the receptors, neuronal apoptosis inhibitory protein (Naip) 5 or Naip6, which activate the Nlrc4 inflammasome multi-protein complex for initiating cell death or interleukin-1 family cytokine release. However, the role of human NAIP as a cytosolic flagellin sensor remains controversial. Using a multipronged approach, we demonstrate that in a reconstituted cell system human NLRC4 engaged Legionella FlaA flagellin directly (i.e. without the need for hNAIP), whereas human NAIP did not interact with FlaA. Ectopic cytosolic FlaA expression also induced NLRC4 oligomerization, a prerequisite for inflammasome activation, in the absence of NAIP. Unexpectedly, the presence of NAIP diminished the binding of NLRC4 to flagellins and subsequent interleukin-1{beta} release. Interestingly, in resting THP-1 cells, NAIP stably interacted with NLRC4, and during infection or stimulation with FlaA pro-inflammatory responses in THP-1 cells were predominantly NLRC4-dependent. Our data highlight NLRC4 as a putative direct sensor of cytosolic flagellins in the human system and NAIP as a potential negative regulator of flagellin sensing.
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BibTeX
@misc{li2026human,
title = {{Human NLRC4 can act as a direct sensor for cytosolic flagellin}},
author = {G. Li and K. Doumanas and X. Liu and N. Panagides and L. Andreeva and F. I. Schmidt and C. E. Bryant and A. N. R. Weber},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.25.746936},
url = {https://www.biorxiv.org/content/10.64898/2026.08.25.746936v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Human NLRC4 can act as a direct sensor for cytosolic flagellin
AU - G. Li
AU - K. Doumanas
AU - X. Liu
AU - N. Panagides
AU - L. Andreeva
AU - F. I. Schmidt
AU - C. E. Bryant
AU - A. N. R. Weber
PY - 2026
DA - 2026/08/25
PB - bioRxiv
DO - 10.64898/2026.08.25.746936
UR - https://www.biorxiv.org/content/10.64898/2026.08.25.746936v2
AB - Innate immune cells sense pathogenic bacteria like Legionella pneumophila through patterns such as the protein flagellin, a critical component of the bacterial motility apparatus. Recognition of cytosolic flagellin in mouse immune cells is well understood and mediated by the receptors, neuronal apoptosis inhibitory protein (Naip) 5 or Naip6, which activate the Nlrc4 inflammasome multi-protein complex for initiating cell death or interleukin-1 family cytokine release. However, the role of human NAIP as a cytosolic flagellin sensor remains controversial. Using a multipronged approach, we demonstrate that in a reconstituted cell system human NLRC4 engaged Legionella FlaA flagellin directly (i.e. without the need for hNAIP), whereas human NAIP did not interact with FlaA. Ectopic cytosolic FlaA expression also induced NLRC4 oligomerization, a prerequisite for inflammasome activation, in the absence of NAIP. Unexpectedly, the presence of NAIP diminished the binding of NLRC4 to flagellins and subsequent interleukin-1{beta} release. Interestingly, in resting THP-1 cells, NAIP stably interacted with NLRC4, and during infection or stimulation with FlaA pro-inflammatory responses in THP-1 cells were predominantly NLRC4-dependent. Our data highlight NLRC4 as a putative direct sensor of cytosolic flagellins in the human system and NAIP as a potential negative regulator of flagellin sensing.
ER -