Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome

Abstract

Val-boroPro (PT-100, Talabostat) induces powerful anti-tumor immune responses in syngeneic cancer models, but its mechanism of action has not yet been established. Val-boroPro is a non-selective inhibitor of post-proline-cleaving serine proteases, and the inhibition of the highly related cytosolic serine proteases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro was recently demonstrated to trigger an immunostimulatory form of programmed cell death known as pyroptosis selectively in monocytes and macrophages. Here we show that Dpp8/9 inhibition activates the inflammasome sensor protein Nlrp1b, which in turn activates pro-caspase-1 to mediate pyroptosis. This work reveals a previously unrecognized mechanism for activating an innate immune pattern recognition receptor and suggests that Dpp8/9 serve as an intracellular checkpoint to restrain Nlrp1b and the innate immune system.

The N-end rule E3 ligase UBR2 activates Nlrp1b inflammasomes

“…Recent studies have established that DPP8/9 inhibitors can activate Nlrp1b inflammasomes and have shown proteasome inhibitors can block this activation 38,39 .…”

Inflammasomes contributing to inflammation in arthritis

“…In the process of activation, the FIIND undergoes self‐cleavage, an event that is required for activation. NLRP1 responds to the enzymatic activities of pathogen effectors such as the lethal toxin (leTox) from Bacillus anthracis and by non‐pathogen‐associated triggers such as the drug Val‐boro‐Pro, an anti‐cancer molecule that inhibits the cytosolic serine proteases Dpp8 and Dpp9 …”

“…NLRP1 responds to the enzymatic activities of pathogen effectors such as the lethal toxin (leTox) from Bacillus anthracis 21 and by non-pathogen-associated triggers such as the drug Val-boro-Pro, an anti-cancer molecule that inhibits the cytosolic serine proteases Dpp8 and Dpp9. 22,23 Gain-of-function mutations within NLRP1 have been described in humans to cause uncontrolled inflammasome activation promoting a familial autoinflammatory skin disease associated with cancer. 24 Other mutations of NLRP1 have been linked to autoinflammation with arthritis and dyskeratosis (AIADK) also known as NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis).…”

Monogenic autoinflammatory disorders: beyond the periodic fever

“…60 PAPA syndrome is caused by heterozygous mutations in PSTPIP1 and although it is understood that the inflammatory manifestations in PAPA syndrome are pyrin dependent, 61,62 the exact mechanism of disease is unclear. [66][67][68][69] An autosomal recessive form of generalised pustular psoriasis has also been described. 63 Two rare dermatological conditions, multiple selfhealing palmoplantar carcinoma and familial keratosis lichenoides chronica, have recently been linked to activating heterozygous mutations in NLRP1.…”

“…Recently, a specific endogenous inhibitor of NLRP1, DPP9, has been identified and it will be interesting to see whether treatment options based on this protein are developed. [66][67][68][69] An autosomal recessive form of generalised pustular psoriasis has also been described. Homozygous missense mutations in IL36RN, causing deficiency in IL-36 receptor antagonist (IL-36Ra, DITRA), lead to unregulated signalling through the IL-36 receptor.…”