A Novel HOIP Frameshift Variant Alleviates NF-kappaB Signaling and Sensitizes Cells to TNF-induced Death

Abstract The linear ubiquitin chain assembly complex (LUBAC) is the sole known complex that can assemble linear ubiquitin chains. It is composed of three distinct subunits: HOIP, SHARPIN, and HOIL-1L, and has a wide range of tissue expression patterns. HOIP, the key component of LUBAC, possesses the capability to form linear ubiquitin linkages. In this study, we report a novel homozygous deletion variant of HOIP that leads to the loss of the catalytic domain of HOIP. The truncated protein could still interact with the other two proteins but was unable to create linear chains. Cells transfected with the truncated protein demonstrated impaired NF-κB activation and MAPK signaling when compared to wild-type cells, as well as sensitivity to TNF-induced death, including apoptosis, necroptosis, and pyroptotic forms of death. This finding provides insight into the genetic range of linear ubiquitination deficiencies in humans and suggests the involvement of cell death in disease pathogenesis.