Human LUBAC deficiency leads to autoinflammation and immunodeficiency by dysregulation in TNF-mediated cell death

Abstract

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage. In mice, the loss of Sharpin leads to severe dermatitis due to excessive cell death in keratinocytes. Here we report the first patient with SHARPIN deficiency, manifesting fever, arthritis, colitis, chronic otitis media and hepatic glycogenosis but unexpectedly, not associated with dermatologic manifestations. Mechanistically, fibroblasts and B cells from patients with all three LUBAC deficiencies showed attenuated canonical NF-κB response and propensity to apoptosis mediated by TNF superfamily members. Furthermore, the SHARPIN deficient patient showed substantial reduction of adenoidal germinal center B cell development. Treatment of the SHARPIN deficient patient with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical role of LUBAC as a gatekeeper for apoptosis-mediated immune dysregulation in humans.

Species-specific LUBAC-mediated M1 ubiquitination regulates necroptosis by segregating the cellular distribution and fate of activated MLKL

“…M1 poly-Ub chains act as a scaffold to recruit signaling complexes, such as the TAK1 complex and the IKK complex to activate downstream MAPK and NF-κB signaling 6,8,9,39,40 . Accordingly, LUBAC deficiency in mice, or in patients with genetic mutations in HOIP, HOIL-1 or Sharpin results in inflammatory disorders linked to deregulated NF-κB activity leading to decreased gene-activatory signaling [30][31][32][41][42][43][44][45] .…”

RIPK1 Biallelic Activating Variants lead to Autoinflammatory Disease Driven by T cell Death

“…Thus, excessive RIPK1-mediated cell death triggered by heterozygous D324 mutations or biallelic K377E and R390G mutations is supposed to be the inducer of autoinflammation. Mutations of genes such as TBK1 8 , OTULIN , HOIP , HOIL1 and SHARPIN 9 , haven been shown to cause several SAIDs. Variants of these genes have been studied in murine models and are revealed to cause embryonic lethality attributed by enhanced cell death 17,25–27 .…”

“…The list of genes whose mutations lead to SAIDs are enriched with key regulators of programmed cell death (PCD). Enhanced PCD is one of the characteristics in the SAID patients caused by the cleavage resistance mutations in RIPK1 3–5 or deficiencies of RIPK1 6,7 , TANK-binding kinase 1 ( TBK1 ) 8 , OTU deubiquitinase with linear linkage specificity ( OTULIN ), HOIL1-interacting protein ( HOIP ), Heme-oxidized IRP2 ubiquitin ligase-1 ( HOIL1 ) and Shank-associated RH domain-interacting protein ( SHARPIN) 9 . Pathogenic variants of these genes have been shown to activate apoptosis and necroptosis in cellular or murine models 10 .…”

Novel functions of LUBAC-mediated M1 poly-ubiquitination in TNFR1-mediated necroptosis

“…Only a few cases of genetic LUBAC deficiencies in human patients have been described thus far. Up till now, only one patient with Sharpin deficiency has been reported [325]. Unexpectedly, this patient showed no signs of dermatologic manifestations but multi-organ inflammation and impaired cellular NF-κB activation [325].…”

“…in deregulated NF-κB activity and decreased gene-activator signaling, leading to inflammatory disorders in both humans and mice [12,235,236,253,270,273,325,326].…”