Mind bomb 1 is essential for generating functional Notch ligands to activate Notch
ABSTRACT The Delta-Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for cell fate specification. Mind bomb 1 (Mib1) has been identified as a ubiquitin ligase that promotes the endocytosis of Delta. We now report that mice lacking Mib1 die prior to embryonic day 11.5, with pan-Notch defects in somitogenesis, neurogenesis, vasculogenesis and cardiogenesis. The Mib1-/- embryos exhibit reduced expression of Notch target genes Hes5, Hey1, Hey2 and Heyl, with the loss of N1icd generation. Interestingly, in the Mib1-/- mutants, Dll1 accumulated in the plasma membrane, while it was localized in the cytoplasm near the nucleus in the wild types, indicating that Mib1 is essential for the endocytosis of Notch ligand. In accordance with the pan-Notch defects in Mib1-/- embryos, Mib1 interacts with and regulates all of the Notch ligands, jagged 1 and jagged 2, as well as Dll1, Dll3 and Dll4. Our results show that Mib1 is an essential regulator, but not a potentiator, for generating functional Notch ligands to activate Notch signaling.
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ABSTRACT: The history of Notch signaling goes back almost a century, to some of the earliest studies of Drosophila development. Since this time, Notch signaling has been found to underlie many evolutionary conserved developmental processes in multiple systems and across phyla. In particular, Notch signaling plays a key role in both invertebrate and vertebrate nervous system development. From the initial identification of its neurogenic phenotype in flies, through recently reported roles in adult mammalian neurogenesis, Notch is best known for mediating lateral inhibition, a process that simultaneously regulates neural differentiation and maintenance of progenitor pools. Here, the authors review these classic functions of Notch, focusing on contributions from higher order vertebrate neurogenic model systems that reveal conserved molecular regulatory pathways similar to those operating in Drosophila. In addition, the authors review Notch's roles in gliogenesis, embryonic stem cells, and exciting new roles in diversifying neuronal subtypes, regulating neuronal morphology, synaptic plasticity, and neuronal activity, revealing that Notch is not(ch) your ordinary signaling pathway.Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS, volume 1 edited by John LR Rubenstein, Pasko Rakic, 01/2013: chapter 17: pages 313-332; Academic Press, Oxford., ISBN: 9780123972651
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ABSTRACT: DSL proteins are transmembrane ligands of the Notch receptor. They associate with a RING (really interesting new gene) family E3 ubiquitin ligase, either Neuralized (Neur) or Mindbomb 1 (Mib1), as a prerequisite to signaling. Although Neur and Mib1 stimulate internalization of DSL ligands, it is not known how ubiquitylation contributes to signaling. We present a molecular dissection of the intracellular domain (ICD) of Drosophila melanogaster Delta (Dl), a prototype DSL protein. Using a cell-based assay, we detected ubiquitylation of Dl by both Neur and Mib1. The two enzymes use distinct docking sites and displayed different acceptor lysine preferences on the Dl ICD. We generated Dl variants that selectively perturb its interactions with Neur or Mib1 and analyzed their signaling activity in two in vivo contexts. We found an excellent correlation between the ability to undergo ubiquitylation and signaling. Therefore, ubiquitylation of the DSL ICD seems to be a necessary step in the activation of Notch.The Journal of Cell Biology 12/2011; 195(6):1017-31. DOI:10.1083/jcb.201105166 · 9.69 Impact Factor
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ABSTRACT: To systematically investigate innate immune signaling networks regulating production of type I interferon, we analyzed protein complexes formed after microbial recognition. Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions; 21% of interactions were modulated by RNA, DNA, or LPS. Overexpression and depletion analyses identified 22 unique genes that regulated NF-κB and ISRE reporter activity, viral replication, or virus-induced interferon production. Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. Mib genes selectively controlled responses to cytosolic RNA. MIB deficiency reduced antiviral activity, establishing the role of MIB proteins as positive regulators of antiviral responses. The HI5 provides a dynamic physical and regulatory network that serves as a resource for mechanistic analysis of innate immune signaling.Immunity 09/2011; 35(3):426-40. DOI:10.1016/j.immuni.2011.06.014 · 19.75 Impact Factor