OTULIN in NF-κB signaling, cell death, and disease

OTULIN is the only DUB that specifically removes linear ubiquitin chains. Loss of OTULIN causes OTULIN-related autoinflammatory syndrome (ORAS) in humans and is lethal in mice. OTULIN functions are cell type specific. OTULIN is crucial for the regulation of nuclear factor (NF)-κB signaling and cell death. OTULIN acts as a tumor suppressor in mouse liver. New ubiquitin-independent functions of OTULIN are emerging. Tight control of inflammatory signaling pathways is an absolute requirement to avoid chronic inflammation and disease. One of the proteins responsible for such control is OTU deubiquitinase with linear linkage specificity (OTULIN), the only mammalian deubiquitinating enzyme (DUB) exclusively hydrolyzing linear ubiquitin chains from proteins modified by the linear ubiquitin chain assembly complex (LUBAC) described thus far. Recent findings show that loss-of-function mutations in OTULIN underlie a severe early-onset human autoinflammatory disease and severe pathology in experimental mouse models. Here, we review the molecular and cellular mechanisms by which OTULIN controls inflammation and discuss the involvement of OTULIN in inflammatory disease development. We also highlight several newly identified roles for OTULIN, including a ubiquitin-independent function. Tight control of inflammatory signaling pathways is an absolute requirement to avoid chronic inflammation and disease. One of the proteins responsible for such control is OTU deubiquitinase with linear linkage specificity (OTULIN), the only mammalian deubiquitinating enzyme (DUB) exclusively hydrolyzing linear ubiquitin chains from proteins modified by the linear ubiquitin chain assembly complex (LUBAC) described thus far. Recent findings show that loss-of-function mutations in OTULIN underlie a severe early-onset human autoinflammatory disease and severe pathology in experimental mouse models. Here, we review the molecular and cellular mechanisms by which OTULIN controls inflammation and discuss the involvement of OTULIN in inflammatory disease development. We also highlight several newly identified roles for OTULIN, including a ubiquitin-independent function. in vitro tissue model of self-renewing mini guts; comprise all cell types of the intestinal epithelium, incorporating many of the physiologically relevant features of the in vivo intestinal tissue; are a physiologically more relevant in vitro system compared with cell line cultures. a key tool used to understand biological contributions stemming from the hematopoietic versus stromal compartment. Mice are irradiated to ablate their bone marrow cells and are subsequently transplanted with bone marrow cells from other mice. Mixed chimerism refers to a state in which genetically different hematopoietic cells are mixed before transplantation. toxic effect of damaged or misfolded proteins or protein aggregates on the cell. sensors that detect foreign nucleic acids and initiate signaling cascades that activate innate host defense. a protein involved in the transport of proteins from the endosome to the plasma membrane, promoting the recycling of internalized transmembrane proteins. process by which a functional group in a substrate contributes to catalysis by an enzyme.