Autophagic suppression of ASC inflammasomes (2016–2018)

Abstract:
The innate immune system protects against infection but also drives inflammatory diseases. A key molecular player in these settings is the ¿¿¿inflammasome¿¿¿, a danger detection system triggering immune system activation via caspase activation, cytokine production and inflammatory cell death. Most inflammasomes signal via the common adaptor, ASC. We and others recently discovered that ASC has unusual prion-like properties; inflammasome-recruited ASC rapidly polymerises into filaments that facilitate signalling both within the cell, and to neighbouring cells upon filament release by cell lysis. The stability of these ASC filaments raises the important question of how inflammasome signalling is turned off upon microbial eradication in healthy individuals, and highlights the clinical challenges for treating patients with inflammasome-driven diseases (e.g. hereditary auto-inflammation, gout, Alzheimer¿¿¿s). Surprisingly, little is known of how cells and tissues deactivate inflammasomes. Our new data reveal a novel pathway for suppressing ASC inflammasome signalling. We found that tyrosine phosphatase inhibition triggers a rapid, near-complete loss of cellular ASC via autophagy, suggesting that a novel phospho-protein switch controls ASC availability for inflammasomes. This new pathway blocked future inflammasome assembly in unstimulated cells, and excitingly, it also deactivated assembled ASC filaments in inflammasome-stimulated cells. Here, we will (1) elucidate the molecular and cellular mechanisms that drive autophagic ASC degradation, (2) identify the phosphatase that suppresses this pathway, and (3) test selective tyrosine phosphatase inhibitors for their potential to block inflammasome-driven inflammation in vitro and in vivo. Achieving these objectives should present new opportunities for intervention in the many human diseases where inflammasomes play pathological roles.
Grant type:
NHMRC Project Grant
Researchers:
  • Professorial Research Fellow
    Institute for Molecular Bioscience
    Affiliate ARC Future Fellow
    School of Chemistry and Molecular Biosciences
    Faculty of Science
Funded by:
National Health and Medical Research Council