Behcet disease (BD) and BD-like clinical phenotypes: NF-kappa B pathway in mucosal ulcerating diseases
SCANDINAVIAN JOURNAL OF IMMUNOLOGY
Authors: Perazzio, Sandro F.; Allenspach, Eric J.; Eklund, Kari K.; Varjosalo, Markku; Shinohara, Michi M.; Torgerson, Troy R.; Seppanen, Mikko R. J.
Abstract
Behcet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namelyHLA-B*51,ERAP1,IL-10,IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNF alpha, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-kappa B activation (egTNFAIP3,NFKB1,OTULIN,RELA,IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-kappa B pathway suggesting new elements in the elusive BD etiopathogenesis.
FAM105A/OTULINL Is a Pseudodeubiquitinase of the OTU-Class that Localizes to the ER Membrane
STRUCTURE
Authors: Ceccarelli, Derek F.; Ivantsiv, Sofiia; Mullin, Amber Anne; Coyaud, Etienne; Manczyk, Noah; Maisonneuve, Pierre; Kurinov, Igor; Zhao, Liang; Go, Chris; Gingras, Anne-Claude; Raught, Brian; Cordes, Sabine; Sicheri, Frank
Abstract
Pseudoenzymes have been identified across a diverse range of enzyme classes and fulfill important cellular functions. Examples of pseudoenzymes exist within ubiquitin conjugating and deubiquitinase (DUB) protein families. Here we characterize FAM105A/OTULINL, the only putative pseudodeubiquitinase of the ovarian tumor protease (OTU domain) family in humans. The crystal structure of FAM105A revealed that the OTU domain possesses structural deficiencies in both active site and substrate-binding infrastructure predicted to impair normal DUB function. We confirmed the absence of catalytic function against all ubiquitin linkages and an inability of FAM105A to bind ubiquitin compared with catalytically active FAM105B/OTULIN. FAM105A co-localized with KDEL markers and Lamin B1 at the endoplasmic reticulum (ER) and nuclear envelope, respectively. Accordingly, the FAM105A interactome exhibited significant enrichment in proteins localized to the ER/outer nuclear, Golgi and vesicular membranes. In light of undetectable deubiquitinase activity, we posit that FAM105A/OTULINL functions through its ability to mediate protein-protein interactions.
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