Research

Pathogens try to escape from our immune system by mutating their proteins. To prevent the bacterium from infecting the cells with a single mutation, the NAIP5 protein of the inflammosome is capable of detecting bacterial flagellin at several sites.

The inflammasome is a large macromolecular complex involved in the elimination of pathogens that try to enter our cells, and those from other animals and plants. It is composed mainly of two types of proteins, NAIP and NLRC4. When the NAIP protein detects a pathogen-specific protein it triggers the assembly of NLRC4 to form a complete inflammasome, which is responsible for initiating the different immune responses, including a type of programmed cell death known as pyroptosis.

There are different types of NAIP proteins to identify different bacterial systems, for example, NAIP1 and NAIP2 bind proteins of the type III secretion system that is used to inject toxins into cells, and NAIP5 detects flagellin, the major protein of flagella , involved in mobility.

Led by professors Eva Nogales and Russell E. Vance of the University of California (Berkeley), the IQFR researchers Pablo Chacón and José Ramón López-Blanco (chaconlab.org) helped to unravel the mechanism by which NAIP5 detects the flagellum of the bacteria and initiates the polymerization of NLRC4. The mechanism of action begins when NAIP5 encounters flagellin, activates and changes shape to act as a primer for NLRC4. Once NLRC4 is activated, a chain reaction begins, in which more monomers of NLRC4 are sequentially joined to generate a complete disk-shaped complex.

In particular, the CSIC researchers have interpreted an electron microscopy map at 5.2 Å resolution obtained by the Berkeley researchers to model the atomic structure of the inflammasome assembly initiator protein NAIP5. The modeled structure has not only determined that NAIP5 is capable of recognizing flagellin using multiple binding sites, up to six, but has made it possible to "see" which specific amino acids are involved in said recognition. Redundancy in the number of anchor points prevents point mutations from eluding the detection of the bacteria by the innate immune system. In addition, the binding sites have evolved to be very similar to those required by flagellin to form a functional flagellum. This way, the innate immune system of plants and animals makes even more difficult the evasion attempts of the bacteria in the never-ending survival war.

JL Tenthorey, N Haloupek, JR López-Blanco, P Grob, E Adamson, E Hartenian, NA Lind, P Chacón, E Nogales, RE Vance (2017). Structural basis of flagellin detection by NAIP5: a strategy to limit pathogen immune evasion. Science 358 (6365), 888-93. DOI: 10.1126/science.aao1140

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