Matsuzawa-Ishimoto et al. show that autophagy gene ATG16L1, which is associated with inflammatory diseases of the gastrointestinal tract, is essential for preventing necroptotic cell death and loss of Paneth cells in the intestinal epithelium.

SUMMARY Determining the factors regulating the rate limiting steps in transcriptional control is of fundamental importance to understanding the mechanisms that govern eukaryotic transcription. While studies in unicellular organisms have pointed to initiation as the rate-limiting step in transcription, a large body of work in metazoans indicates that the transition to productive transcriptional elongation may also constitute a critical step. Here, we show that the RNA polymerase II (RNAPII)-associated multi-protein complex, Integrator, plays a critical role in both initiation and the release of paused RNAPII in immediate early genes (IEGs) following transcriptional activation by epidermal growth factor (EGF) in human cells. Integrator is recruited to the IEGs in a signal-dependent manner and is required to engage the super elongation complex (SEC) in pause release. We propose a role for Integrator as an RNAPII-associated factor modulating both initiation and pause release during transcriptional activation in metazoans.

Summary Pancreatic ductal adenocarcinoma (PDA) is characterized by immune-tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine-protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T-helper cell differentiation towards a mixed Th1/Th17 phenotype, leading to tumor-immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1- and ICOS-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor-immunity.

Background: The inability to coordinate the signaling pathways that lead to proper cytokine responses characterizes the pathogenesis of inflammatory diseases such as Crohn's Disease. The Crohn's Disease susceptibility protein, NOD2, helps coordinate cytokine responses upon intracellular exposure to bacteria, and this signal coordination by NOD2 is accomplished, in part, through K63-linked polyubiquitin chains that create binding surfaces for the scaffolding of signaling complexes. Results: In this work, we show that the NOD2 signaling partner, RIP2, is directly K63 polyubiquitinated by ITCH, an E3 ubiquitin ligase which when lost genetically, causes widespread inflammatory disease at mucosal surfaces. We show that ITCH is responsible for RIP2 polyubiquitination in response to infection with listeria monocytogenes. We further show that NOD2 can bind polyubiquitinated RIP2, and while ITCH E3 ligase activity is required for optimal NOD2:RIP2-induced p38 and JNK activation, ITCH inhibits NOD2:RIP2-induced NFκB activation. This effect can be seen independently at the whole genome level by microarray analysis of MDP-treated Itch−/− primary macrophages. Conclusions: These findings suggest that ITCH helps regulate NOD2-dependent signal transduction pathways and as such, may be involved in the pathogenesis of NOD2-mediated inflammatory disease.