13. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. Abstract Mycobacterium tuberculosis PtpA, a secreted tyrosine phosphatase essential for tuberculosis pathogenicity, could be an id eal target for a drug against tuberculosis, but its active-site inhibitors lack selectivity over human phosphatases. Here we f ound that PtpA suppressed innate immunity dependent on pathways of the kinases Jnk and p38 and the transcription fact or NF-κB by exploiting host ubiquitin. Binding of PtpA to ubiquitin via a region with no homology to human proteins activate d it to dephosphorylate phosphorylated Jnk and p38, leading to suppression of innate immunity. Furthermore, the host ada ptor TAB3 mediated NF-κB signaling by sensing ubiquitin chains, and PtpA blocked this process by competitively binding t he ubiquitin-interacting domain of TAB3. Our findings reveal how pathogens subvert innate immunity by coopting host ubiq uitin and suggest a potential tuberculosis treatment via targeting of ubiquitin-PtpA interfaces.

14. National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Abstract Immune responses need to be tightly controlled to avoid excessive inflammation and prevent unwanted host damage. Her e we report that germinal center kinase MST4 responded dynamically to bacterial infection and acted as a negative regula tor of inflammation. We found that MST4 directly interacted with and phosphorylated the adaptor TRAF6 to prevent its olig omerization and autoubiquitination. Accordingly, MST4 did not inhibit lipopolysaccharide-induced cytokine production in Tr af6 −/− embryonic fibroblasts transfected to express a mutant form of TRAF6 that cannot be phosphorylated at positions 46 3 and 486 (with substitution of alanine for threonine at those positions). Upon developing septic shock, mice in which MST 4 was knocked down showed exacerbated inflammation and reduced survival, whereas heterozygous deletion of Traf6 (Tr af6 +/− ) alleviated such deleterious effects. Our findings reveal a mechanism by which TRAF6 is regulated and highlight a ro le for MST4 in limiting inflammatory responses.

18. [Science] 27 FEBRUARY 2015 VOL 347, ISSUE 6225, PAGES 921-1040

23. [Science] 20 FEBRUARY 2015 VOL 347, ISSUE 6224, PAGES 801-920 Autophagy or not? Under low glucose conditions (starvation), the degradation of insulin granules in β cells leads to the production of amino acids, the local activation of mTORC1, and suppression of autophagy, which removes a signal for insulin release and ensures cell survival. In non–nutrient-sensing cells, the same condition activates autophagy to ensure survival.

24. [Science] 20 FEBRUARY 2015 VOL 347, ISSUE 6224, PAGES 801-920