Human NLRP1 is a sensor for double-stranded RNA

Abstract

Inflammasomes function as intracellular sensors of pathogen infection or cellular perturbation and thereby play a central role in numerous diseases. Given the high abundance of NLRP1 in epithelial barrier tissues, we screened a diverse panel of viruses for inflammasome activation in keratinocytes. We identified Semliki Forest virus (SFV), a positive-strand RNA virus, as a potent activator of human, but not murine NLRP1. SFV replication and the associated formation of double-stranded (ds) RNA was required to engage the NLRP1 inflammasome. Moreover, delivery of long dsRNA was sufficient to trigger activation. Biochemical studies revealed that NLRP1 binds dsRNA via its LRR, resulting in its NACHT domain gaining ATPase activity. Altogether, these results establish human NLRP1 as a direct sensor for dsRNA and thus RNA virus infection.

Diverse viral proteases activate the NLRP1 inflammasome

“…Additional recent work has indicated that dsRNA can also activate the NLRP1 inflammasome in human keratinocytes (Bauernfried, Scherr, Pichlmair, Duderstadt, & Hornung, 2020), adding to the role that NLRP1 may play in the inflammatory response. Beyond the skin, NLRP1 is also basally expressed in tissues such as the gut and brain (D'Osualdo et al, 2015;Kaushal et al, 2015;Kummer et al, 2007), which are sites of picornavirus replication where overactivation upon infection may result in immunopathology.…”

“…Here, germline mutations in NLRP1 that result in overactivation can cause growth of warts in the upper airway in a condition known as recurrent respiratory papillomatosis (JRRP) ( Drutman et al, 2019 ) and an increase in skin cancer susceptibility and skin disorders such as multiple self-healing palmoplantar carcinoma (MSPC), familial keratosis lichenoides chronica (FKLC) and auto-inflammation with arthritis and dyskeratosis (AIADK) ( Grandemange et al, 2017 ; Herlin et al, 2020 ; Soler et al, 2013 ; Zhong et al, 2016 ; Zhong et al, 2018 ). Additional recent work has indicated that dsRNA can also activate the NLRP1 inflammasome in human keratinocytes ( Bauernfried et al, 2020 ), adding to the role that NLRP1 may play in the inflammatory response. Beyond the skin, NLRP1 is also basally expressed in tissues such as the gut and brain ( D'Osualdo et al, 2015 ; Kaushal et al, 2015 ; Kummer et al, 2007 ), which are sites of picornavirus replication where overactivation upon infection may result in immunopathology.…”

NLRP1: a jack of all trades, or a master of one?

“…Human nucleotide-binding domain leucine-rich repeat pyrin domain-containing 1 (hNLRP1) was the first PRR discovered to form an inflammasome (Martinon et al, 2002), but the danger signal that activates hNLRP1 has eluded identification for nearly 20 years. Two recent studies provide evidence that hNLRP1 directly senses (at least) two extraordinarily different things: enteroviral 3C protease activity (Robinson et al, 2020) and long double-stranded RNA (dsRNA) (Bauernfried et al, 2020).…”

DPP9 deficiency: an Inflammasomopathy which can be rescued by lowering NLRP1/IL-1 signaling

“…The human NLRP1 inflammasome is a multi-protein complex that is triggered by viral infections( 1, 2) , or danger-associated signals( 3 ), resulting in the release of proinflammatory cytokines, including IL-1 family members, IL-1β and IL-18( 4 ). Dysregulation of the human NLRP1 inflammasome is associated with a range of inflammatory Mendelian diseases such as Multiple Self-healing Palmoplantar Carcinoma (MSPC, MIM615225)( 5 ), Juvenile Recurrent Respiratory Papillomatosis (JRRP, 618803MIM)( 6 ), and Autoinflammation with Arthritis and Dyskeratosis (AIADK, MIM617388)( 7 ).…”