Explanation of the relationship between NOD2, NLRC4, T3SS, and bacterial pathogens:

By SWA

Explanation for: Yao Syndrome: A Comprehensive Overview

The NOD2 gene's normal function is to sense bacterial components and trigger an immune response to fight infection. Its dysfunction, caused by genetic mutations, can lead to an overactive (gain-of-function) or underactive (loss-of-function) immune response.

NOD2 and NLRC4 are both intracellular immune receptors that help the host detect bacterial infections and initiate immune responses. While they function through different mechanisms, recent evidence shows they can interact and influence each other, especially during bacterial infections.

  • NOD2 is known for recognizing bacterial peptidoglycan components (specifically muramyl dipeptide, MDP) and plays a key role in maintaining immune balance. Mutations in NOD2 are linked to inflammatory diseases like Crohn’s disease.

  • NLRC4, on the other hand, forms part of a larger protein complex called the inflammasome, which activates inflammatory responses, including the release of IL-1β and IL-18. The NLRC4 inflammasome is specifically activated by flagellin and proteins secreted through the Type III Secretion System (T3SS) of certain gram-negative bacterial pathogens.

T3SS and Pathogens:

The Type III Secretion System (T3SS) is a specialized structure used by many gram-negative bacteria (e.g., Salmonella, Shigella, Yersinia, Pseudomonas, Legionella) to inject effector proteins directly into host cells. This system acts like a molecular syringe, allowing bacteria to:

  • Manipulate host cell signaling

  • Escape immune detection

  • Avoid destruction inside immune cells

These T3SS-delivered proteins can be recognized by NAIP proteins in the host cell, which then trigger NLRC4 activation. This leads to inflammasome formation, cytokine release, and sometimes pyroptosis, a form of programmed cell death that helps eliminate infected cells.

NOD2 and NLRC4 Interaction:

Recent studies suggest that NOD2 can interact with NLRC4, possibly modulating its activation or enhancing the host's ability to respond to pathogens that use T3SS. This cooperation helps amplify the immune response to bacteria that evade or manipulate the immune system using their secretion systems.

In Summary:

  • Bacterial pathogens (like Salmonella, Shigella) use T3SS to inject virulence factors into host cells.

  • These factors are detected by NLRC4, which forms an inflammasome to trigger inflammation.

  • NOD2, another innate immune sensor, can interact with NLRC4, potentially enhancing or regulating this response.

  • Together, these systems help the host recognize and respond to harmful intracellular bacteria, making them key players in innate immunity.

References:

Updating the NLRC4 Inflammasome: from Bacterial Infections to Autoimmunity and Cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC8283967/

Type III Secretion System | Definition & Function
https://study.com/academy/lesson/type-iii-secretion-system-definition-function.html

Process of Type III Secretion
https://www.youtube.com/watch?v=OBf64TEo7gA&t=6s

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742

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