DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages

Vasconcelos, Nathalia Moraes de; Vliegen, Gwendolyn; Gonçalves, Amanda; Hert, Emilie De; Martín-Pérez, Rosa; Opdenbosch, Nina Van; Jallapally, Anvesh; Geiss‐Friedlander, Ruth; Lambeir, Anne‐Marie; Augustyns, Koen; Veken, Pieter Van der; Meester, Ingrid De; Lamkanfi, Mohamed

doi:10.26508/lsa.201900313

Cited by 50 publications

(43 citation statements)

References 48 publications

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“…[113][114][115] In addition, inhibition of host serine proteases DPP8/9 leads to a similar proteasomal-dependent activation of multiple variants of NLRP1, including those not sensitive to anthrax LF. [116][117][118] Pyrin. Activation of the Pyrin inflammasome is also controlled without direct binding between Pyrin and a bacterial ligand.…”

Section: Activation Of Aim2 and Naip-nlrc4 By Ligand Bindingmentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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Inflammasomes are multi-component signaling complexes critical to the initiation of pyroptotic cell death in response to invading pathogens and cellular damage. A number of innate immune receptors have been reported to serve as inflammasome sensors. Activation of these sensors leads to the proteolytic activation of caspase-1, a proinflammatory caspase responsible for the cleavage of proinflammatory cytokines interleukin-1β and interleukin-18 and the effector of pyroptotic cell death, gasdermin D. Though crucial to the innate immune response to infection, dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. Therefore, clinical interest in the modulation of inflammasome activation is swiftly growing. As such, it is imperative to develop a mechanistic understanding of the regulation of these complexes. In this review, we divide the regulation of inflammasome activation into three parts. We discuss the transcriptional regulation of inflammasome components and related proteins, the post-translational mechanisms of inflammasome activation, and advances in the understanding of the structural basis of inflammasome activation.

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Section: Activation Of Aim2 and Naip-nlrc4 By Ligand Bindingmentioning

confidence: 99%

Toward targeting inflammasomes: insights into their regulation and activation

2020

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“…In agreement, boronic acid peptides such as Val-boroPro (also known as Talabostat) that inhibit DPP8/9 as well as several other DPP family members, and the DDP8/9-selective inhibitor 1G244 activate human NLRP1 and the murine NLRP1b inflammasomes. [22][23][24][25] Activation of human NLRP1 and murine NLRP1b is thought to involve proteasomal degradation of the auto-inhibitory amino-terminal region, which enables the recruitment of ASC and caspase-1 to their carboxy-terminal UPA-CARD-containing regions (Figure 1). 26,27 A homozygous NLRP1 gain-of-function mutation was recently reported to cause an autosomal recessive form of juvenile-onset recurrent respiratory papillomatosis in two siblings with mild dermatologic abnormalities.…”

Section: Nlrp1mentioning

confidence: 99%

Therapeutic modulation of inflammasome pathways

Chauhan

Walle

Lamkanfi

2020

Immunological Reviews

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160

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Inflammasomes are macromolecular complexes formed in response to pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs) that drive maturation of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, and cleave gasdermin D (GSDMD) for induction of pyroptosis. Inflammasomes are highly important in protecting the host from various microbial pathogens and sterile insults. Inflammasome pathways are strictly regulated at both transcriptional and post‐translational checkpoints. When these checkpoints are not properly imposed, undue inflammasome activation may promote inflammatory, metabolic and oncogenic processes that give rise to autoinflammatory, autoimmune, metabolic and malignant diseases. In addition to clinically approved IL‐1‐targeted biologics, upstream targeting of inflammasome pathways recently gained interest as a novel pharmacological strategy for selectively modulating inflammasome activation in pathological conditions.

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“…Dipeptidyl peptidases 9 (DPP9) is an intracellular protease of the DPPIV family, that is critical for neonatal survival (Gall et al 2013) with roles in the immune response (Geiss-Friedlander et al 2009;Okondo et al 2016;Okondo et al 2018;Johnson et al 2018;de Vasconcelos et al 2019). Deregulation of DPP9 is connected to pathophysiological conditions such as tumorigenicity (Tang et al 2017;Smebye et al 2017;Johnson et al 2018;Spagnuolo et al 2013), whereby the underlying mechanisms are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl peptidase 9 triggers BRCA2 degradation by the N-degron pathway to promote DNA-damage repair

Silva-Garcia

Bolgi

Ross

et al. 2020

Preprint

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Dipeptidyl peptidase 9 (DPP9) is a serine protease cleaving N-terminal dipeptides preferentially post-proline with (patho)physiological roles in the immune system and cancer. Only few DPP9 substrates are known. Here we identify an association of human DPP9 with the tumour suppressor BRCA2, a key player in repair of DNA double-strand breaks that promotes the formation of RAD51 filaments. This interaction is triggered by DNA-damage and requires access to the DPP9 active-site. We present crystallographic structures documenting the N-terminal Met1-Pro2 of a BRCA21-40 peptide captured in the DPP9 active-site. Mechanistically, DPP9 targets BRCA2 for degradation by the N-degron pathway, and promotes RAD51 foci formation. Both processes are phenocopied by BRCA2 N-terminal truncation mutants, indicating that DPP9 regulates both stability and the cellular stoichiometric interactome of BRCA2. Consistently, DPP9-deprived cells are hypersensitive to DNA-damage. Together, we identify DPP9 as a regulator of BRCA2, providing a possible explanation for DPP9 involvement in cancer development.

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DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages

Abstract: This study shows that caspase-1 autocleavage, ASC speck assembly, and mature IL-1β and IL-18 secretion accompany rapid DPP8/DPP9-regulated pyroptosis induction in macrophages expressing a LeTx-responsive Nlrp1b allele.

Cited by 50 publications

References 48 publications

Toward targeting inflammasomes: insights into their regulation and activation

Toward targeting inflammasomes: insights into their regulation and activation

Therapeutic modulation of inflammasome pathways

Dipeptidyl peptidase 9 triggers BRCA2 degradation by the N-degron pathway to promote DNA-damage repair

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