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Decoding Ubiquitin Networks in regulation of inflammation and autophagy
Author(s) -
Dikic Ivan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.94.1
Subject(s) - autophagy , ubiquitin , microbiology and biotechnology , optineurin , mitophagy , cytosol , parkin , lysosome , kinase , proteasome , biology , chemistry , biochemistry , gene , enzyme , medicine , apoptosis , disease , pathology , parkinson's disease
Ubiquitin acts as a cellular signal that is decoded by its receptors to control normal functioning of the cell via different linkage types. Using the different structural and biochemical properties of different ubiquitin chain linkages, we have developed fluorescence‐based sensors to monitor real‐time localization and dynamics of ubiquitination events in vivo. For example, linear chain‐specific sensors labeled the ubiquitin coat surrounding cytosolic Salmonella and were also able to block TNF‐induced NF‐κB activation; whereas K63‐sensors were enriched at DNA double strand breaks and depolarized mitochondria following Parkin recruitment. In addition to sensors that detect linkage‐specific ubiquitin chains, we have been exploring the fate of intracellular pathogens and how they are targeted by the host autophagy system. Removal of harmful protein aggregates, damaged organelles and microbes is mediated by autophagy, a process by which the cell sequesters cytosolic cargo and delivers it for degradation by the lysosome. Optineurin, a new autophagy receptor, together with p62 and NDP52, mediates selective autophagy of ubiquitin‐coated cytosolic Salmonella enterica. The protein kinase TBK1 (TANK binding kinase 1) was shown to mediate phosphorylation of both LC3‐ and Ub‐binding domains to ensure a rapid engulfment of cytosolic bacteria and efficient autophagic clearance.