Within the cytoplasm of our cells, protein complexes known as inflammasomes function as alarm systems for the innate immune system. They are a first line of defense, detecting cellular danger and initiating an inflammatory response. One specialized alarm is the NLRC4 inflammasome, which is attuned to detecting dangerous bacteria that have invaded the cell’s interior. Its primary function is to recognize molecular signs of bacterial presence and orchestrate a counter-attack to eliminate the compromised host cell and expose the bacteria to the wider immune system.
Core Components and Assembly of the NLRC4 Inflammasome
The NLRC4 inflammasome is constructed from several protein components. The central protein is NLRC4, which acts as the foundational scaffold for the entire structure. In its inactive state, NLRC4 exists as a dormant unit within the cell’s cytoplasm.
Another component is Caspase-1, an enzyme responsible for executing the inflammasome’s effects. Its inactive precursor, pro-caspase-1, is present in the cytosol awaiting a signal. The activation of Caspase-1 is the objective of the inflammasome’s assembly.
When the system is triggered, multiple NLRC4 proteins join together in a process called oligomerization, forming a large, wheel-like structure. This wheel acts as a platform to recruit pro-caspase-1 molecules, bringing them into close proximity for activation.
The initial trigger causes the first NLRC4 proteins to connect, encouraging more to join until the structure is complete. In some contexts, an adaptor protein called ASC can act as a bridge between the NLRC4 wheel and pro-caspase-1. The NLRC4 platform can also recruit Caspase-1 directly through interactions between specialized domains known as CARDs.
Activation by Pathogen Signatures
The NLRC4 protein does not directly recognize bacterial invasion. It relies on sensor proteins called NAIPs (NLR family apoptosis inhibitory proteins) to act as the primary detectors. Each NAIP is specialized to identify specific molecular signatures of bacteria inside the cell. The binding of a bacterial molecule to its corresponding NAIP is the trigger that initiates inflammasome assembly.
One well-studied activator is flagellin, the protein subunit that forms the flagellum used by bacteria like Salmonella for motility. These pathogens are detected if flagellin monomers enter the host cell’s cytoplasm. Specific NAIP proteins in mice and a variant of the human NAIP are responsible for directly binding to flagellin.
NAIPs also detect bacterial secretion systems. Pathogens like Shigella and Legionella use Type III or Type IV secretion systems (T3SS/T4SS) to inject virulence factors into host cells. NAIP proteins recognize components of these injection devices, such as the needle and inner rod proteins.
For instance, human NAIP can detect the T3SS needle protein from bacteria like Salmonella and Burkholderia. This binding induces a conformational change in the NAIP protein, enabling it to interact with and activate the first NLRC4 molecule. This interaction starts the chain reaction of inflammasome assembly.
Executing the Immune Response
Once assembled, the NLRC4 inflammasome activates Caspase-1, unleashing a two-pronged immune response. Active Caspase-1 functions as a molecular scissor, cleaving other proteins to activate them. This results in the release of signaling molecules and a specialized form of cell death to control the infection.
The first outcome is the release of pro-inflammatory cytokines. Caspase-1 cleaves the inactive precursors pro-Interleukin-1β (pro-IL-1β) and pro-Interleukin-18 (pro-IL-18), generating their mature forms. These cytokines are secreted from the cell to alert the immune system. IL-1β is effective at recruiting neutrophils, while IL-18 stimulates other immune cells to produce defensive molecules.
The second consequence of Caspase-1 activation is an inflammatory form of programmed cell death called pyroptosis. Caspase-1 cleaves a protein called Gasdermin D, unleashing a fragment that inserts itself into the cell’s plasma membrane. Multiple Gasdermin D fragments then join together to form large pores.
These pores disrupt the cell’s integrity, causing it to swell and burst. This lytic death eliminates the infected cell and physically expels the invading bacteria from their hiding place. Once outside, the bacteria are exposed to recruited immune cells and other antimicrobial factors for destruction.
Implications in Human Disease
The regulation of the NLRC4 inflammasome is important for health, as its dysregulation is linked to human diseases. This imbalance can manifest as either excessive activity, leading to autoinflammatory conditions, or insufficient activity, resulting in heightened susceptibility to infection.
Genetic “gain-of-function” mutations can cause the NLRC4 protein to be inherently overactive, removing the safety checks that prevent activation. This leads to spontaneous inflammasome assembly and chronic, unwarranted inflammation. Patients with these mutations suffer from disorders known as NLRC4-inflammasomopathies, causing symptoms like recurrent fevers, severe gut inflammation, and macrophage activation syndrome (MAS).
Conversely, a deficient NLRC4 pathway can leave a person vulnerable. “Loss-of-function” mutations impair the body’s ability to respond to the specific bacteria it targets. This can lead to increased susceptibility to infections by pathogens like Salmonella that use flagella or Type III secretion systems. Without a robust NLRC4 response, the immune system is slower to clear these infections, potentially leading to more severe disease.