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Colored scanning electron micrograph of rhinoviruses (yellow) on nasal epithelial cells (blue). Researchers have now identified NLRP1 as the body's rhinovirus sensor.

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NLRP1: How the body senses the common cold virus

28 Jun 2021

The mysterious trigger of the NLRP1 inflammasome sensor has finally been identified: a protease found in the common cold-causing human rhinovirus tells our body that it has been invaded.

Whether in business, military combat, or the body’s immune response, all good defense strategies deploy multiple lines of defense. With the main goal of identifying risks, the body’s first line of defense—the innate immune system—uses special protein sensors to detect pathogens that have breached the body’s physical barriers, which activates the next level of immune response.

One class of sensors, known as Nodlike receptor (NLR) proteins, play an important role in inflammation. They cause the assembly of multiprotein structures called inflammasomes that stimulate the secretion of inflammatory signals and cell death. To date, several different NLR proteins and their triggers have been identified, showing that NLRs play an important role in the detection of threats ranging from bacteria to viruses and even stress like metabolic dysregulation. However, although it was the first NLR to be discovered in humans, the specific trigger of NLRP1 had remained elusive.

Noting that mutations in NLRP1 tend to cause inflammation in the skin and airways, a team of researchers from A*STAR, the National University of Singapore, and Nanyang Technological University (NTU) hypothesized that pathogens commonly found in those areas might activate NLRP1. They zeroed in on human rhinovirus, a virus responsible for the common cold. As the most frequent human disease, rhinoviruses are estimated to result in up to 75–100 million physician visits annually in the US alone.

Through a series of genetic and cell culture experiments, the researchers found that a rhinovirus enzyme called 3C protease activates NLRP1 by cutting the protein at a single site. This cleavage produces a fragment that is recognized by a protein complex called cullinZER1/ZYG11B, ultimately marking the fragment for degradation. The degradation in turn leads to the full assembly and activation of the NLRP1 inflammasome.

“NLRP1 can be said to serve as a tripwire trigger, sensing pathogen proteases that are infecting the human body,” explained Bruno Reversade, a Research Director at A*STAR’s Institute of Molecular and Cellular Biology (IMCB) and Genome Institute of Singapore (GIS), and lead author of the study with co-corresponding author Franklin Zhong of NTU and the Skin Research Institute of Singapore (SRIS). “Our findings challenge the paradigm that viral proteases are predominantly present for disabling the host immune response, showing that this protease actually triggers NLRP1 as well.”

The study also highlights the important differences between human and mouse immune systems, as the equivalent of NLRP1 in mice is not activated by viral proteases. “This is a reminder that mouse models may not always properly recapitulate human diseases,” Reversade added.

The researchers aim to develop a drug to block NLRP1 activity, as it has been implicated in several inflammatory diseases.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cellular Biology (IMCB), Genome Institute of Singapore (GIS) and the Skin Research Institute of Singapore (SRIS).

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References

Robinson, K.S., Teo, D.E.T., Tan, K.S., Toh, G.A., Ong, H.H., et al. Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia. Science 370, eaay2002 (2020) | article

About the Researcher

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Bruno Reversade

Research Director

Institute of Medical Biology
Bruno Reversade is a Research Director at A*STAR’s Genome Institute of Singapore (GIS) and Institute of Molecular and Cell Biology (IMCB). Trained at the Pasteur Institute in Paris, Reversade obtained his PhD degree from the University Pierre & Marie Curie in France. While at the Howard Hughes Medical Institute in UCLA, he published landmark papers that provide an explanation for how embryonic homeostasis is maintained and how, from one egg, identical twins can be produced. Reversade’s current research involves rare human pedigrees, which suggest that the birth of monoclonal humans (identical twins) may be genetically triggered. His work is supported by the Branco Weiss Foundation, whose mission is to bridge science and society. Reversade was awarded the inaugural A*STAR Research Investigatorship in 2008; he joined IMB in the same year as a Principal Investigator, and he was promoted to Senior Principal Investigator in 2012.

This article was made for A*STAR Research by Wildtype Media Group