Nat Med. 2016 Aug;22(8):906-14. doi: 10.1038/nm.4141. Epub 2016 Jul 18.
Xiao, Y; Tang, J; Guo, H; Zhao, Y; Tang, R; Ouyang, S; Zeng, Q; Rappleye, CA; Rajaram, MV; Schlesinger, LS; Tao, L; Brown, GD; Langdon, WY; Li, BT; Zhang, J
Ohio State University, Columbus, Ohio, USA. Central South University, Changsha, P.R. China. Guangzhou Medical University, Guangzhou, P.R. China. University of South China, Changsha, P.R. China. University of Aberdeen, Aberdeen, UK. University of Western Australia, Crawley, Western Australia, Australia.
Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 350 scientific publications are based on research using Ozgene mice.