New Immune Response Pathway Uses Gasdermin D

A new line of defence deployed by the immune system against bacteria has been identified in a University of Queensland study. The new understanding of one of the body’s immune defence mechanisms could lead to the development of novel therapeutic targets for conditions such as cancer and autoimmune diseases.

“Bacteria are often quickly killed by white blood cells called neutrophils, which are the body’s initial line of defence against infection. We discovered an unexpected secondary line of defence that is deployed against bacteria that have evaded the initial immune response and invaded the neutrophil itself.

This new immune defence pathway is mediated by an ‘executioner’ protein called Gasdermin D. This protein drives an unusual form of ‘cellular suicide’, where the cell expels structures called neutrophil extracellular traps (NETs) to catch the infection and prevent it from spreading,”

said Associate Professor Kate Schroder, of UQ’s Institute for Molecular Bioscience.

Neutrophil Extracellular Traps

NETs are networks of DNA fibres embedded with antimicrobial proteins that immobilise and kill bacteria, providing a secondary line of resistance.

While researchers already knew that neutrophil cell death can be associated with NETs, this discovery revealed an entirely new pathway using Gasdermin D and the inflammasome – a molecular machine that senses and responds to infection.

Dr. Schroder said while NETs had a protective role in fighting pathogens, they could also drive pathology in some autoimmune and inflammatory diseases, as well as cancers.

“It’s important we understand the basic cellular mechanisms of inflammation before we develop treatments for various immune-related diseases. Understanding how the Gasdermin D drives neutrophil death and the expulsion of NETs could lead to new therapeutic targets for immune-related diseases, which could in turn lead to more effective treatments and improve quality of life for affected individuals,”

Dr. Schroder said.

Gasdermin D

Gasdermin D (GSDMD) is a protein that in humans is encoded by the GSDMD gene on chromosome 8. It belongs the gasdermin family which is conserved among all vertebrates and comprises six members, GSDMA, GSDMB, GSDMC, GSDMD, DFNA5 and DFNB59. Members of the gasdermin family are mainly expressed in epithelial tissues and appear to play a role in regulation of epithelial proliferation and differentiation. GSDMA, GSDMC, GSDMD and DFNA5 have been suggested to act as tumour suppressors.

GSDMD can be cleaved and activated by inflammatory caspases through both the canonical and non-canonical pyroptotic pathways.

Caspase-11 in mice and its human homolog caspase-4 and -5 are involved in the non-canonical pathway and are activated by directly binding cytosolic lipopolysaccharide (LPS) secreted by gram-negative bacteria.

Overview of GSDMD activation and pore-forming mechanism

Overview of GSDMD activation and pore-forming mechanism
Credit: Nataliechui619 CC BY-SA 4.0

Upon activation of these caspases, GSDMD undergoes proteolytic cleavage at Asp-275, which is sufficient to drive pyroptosis.

Pyroptosis, which can now be defined as gasdermin-mediated necrotic cell death, acts as an immune defence against infection. Hence, failure to express or cleave GSDMD can block pyroptosis and disrupt the secretion of IL-1β, and eventually unable to ablate the replicative niche of intracellular bacteria.

Mutation of GSDMD is associated with various genetic diseases and human cancers, including brain, breast, lung, urinary bladder, cervical, skin, oral cavity, pharynx, colon, liver, cecum, stomach, pancreatic, prostate, oesophageal, head and neck, hematologic, thyroid and uterine cancers.

The research was supported by the National Health and Medical Research Council of Australia, Senior Research Fellowship, and Career Development Fellowship and the Australian Research Council.

Kaiwen W. Chen, Mercedes Monteleone, Dave Boucher, Gabriel Sollberger, Divya Ramnath, Nicholas D. Condon, Jessica B. von Pein, Petr Broz, Matthew J. Sweet, Kate Schroder
Noncanonical inflammasome signaling elicits gasdermin D–dependent neutrophil extracellular traps
Science Immunology 24 Aug 2018: Vol. 3, Issue 26, eaar6676 DOI: 10.1126/sciimmunol.aar6676

Top Image: University of Edinburgh. CC BY-NC

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