Author response: Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis

Abstract

Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD-and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpindeficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes.

ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis)

“…Similarly, genetic deficiency of the NF-κB and MAPK components suggests a role for the necrosome components RIPK1 and RIPK3 in promoting NLRP3 inflammasome activation, triggering multiple forms of cell death and the development of inflammatory diseases (Ikeda et al, 2011; Matmati et al, 2011; Tokunaga et al, 2011; Vince et al, 2012; Kumari et al, 2014; Rickard et al, 2014; Vande Walle et al, 2014; Gurung et al, 2015; Xu et al, 2018; Peltzer and Walczak, 2019; Polykratis et al, 2019; Yuan et al, 2019). Similarly, disease in Pstpip2 cmo mice, which have a missense mutation in the proline-serine-threonine phosphatase-interacting protein 2 ( Pstpip2 ) gene that results in debilitating inflammatory arthritis similar to that of patients with chronic multifocal osteomyelitis (cmo), is rescued when caspase-8 is inactivated in combination with either caspase-1 or the NLRP3 inflammasome (Ferguson et al, 2006; Grosse et al, 2006; Lukens et al, 2014; Gurung et al, 2016).…”