NLRP1

NLRP1 forms an inflammasome platform with caspase-1, caspase-5, ASC/PYCARD, and NALP1 to process pro-IL-1β^[1]. Mechanistically, NLRP1 activation can follow functional degradation, where proteasome-mediated N-terminal degradation releases a C-terminal fragment that activates caspase-1^[2]. Human NLRP1 also senses long double-stranded RNA, linking the inflammasome to antiviral innate immune detection^[3]. In primary human keratinocytes, NLRP1 rather than NLRP3 drives UVB sensing and IL-1β/IL-18 secretion, defining a key isoform distinction for skin inflammation models^[4]. Disease studies connect human NLRP1 mutations with NLRP1-associated autoinflammation with arthritis and dyskeratosis and with syndromic recurrent respiratory papillomatosis through gain-of-function inflammasome activation^[5][6]. For experimental applications, DPP9 represses NLRP1 through peptidase activity and FIIND-domain binding, whereas DPP8/9 inhibition activates human NLRP1, induces ASC specks, pyroptotic cell death, and cleaved IL-1β secretion^[7]. Structural work further shows that DPP9 sequesters the NLRP1 C terminus and that NLRP1 binding plus DPP9 enzymatic activity suppress inflammasome activation^[8][9].

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