Ligand-Independent Mechanisms of Notch Activity

Palmer, William H.; Deng, Wu-Min

doi:10.1016/j.tcb.2015.07.010

Cited by 65 publications

(49 citation statements)

References 89 publications

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“…However, the role of Notch signaling in crystal cell growth and survival has been mainly investigated in the larval lymph gland [30, 31]. In agreement with these investigations, inhibiting the Notch pathway in circulating Lz + cells, either by down-regulating the expression of Suppressor of Hairless [Su(H)], the core transcription factor in the Notch pathway, or by overexpressing Suppressor of Deltex [Su(dx)], a negative regulator of Notch [45], resulted in a decrease in lz>GFP + cell number and impaired their growth, whereas the overactivation of Notch signaling consecutive to the expression of a constitutively active Su(H)-VP16 fusion protein [46], caused a strong increase in lz>GFP + cell number and size (S5 Fig). …”

Section: Resultsmentioning

confidence: 99%

Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

et al. 2017

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A tight regulation of transcription factor activity is critical for proper development. For instance, modifications of RUNX transcription factors dosage are associated with several diseases, including hematopoietic malignancies. In Drosophila, Myeloid Leukemia Factor (MLF) has been shown to control blood cell development by stabilizing the RUNX transcription factor Lozenge (Lz). However, the mechanism of action of this conserved family of proteins involved in leukemia remains largely unknown. Here we further characterized MLF’s mode of action in Drosophila blood cells using proteomic, transcriptomic and genetic approaches. Our results show that MLF and the Hsp40 co-chaperone family member DnaJ-1 interact through conserved domains and we demonstrate that both proteins bind and stabilize Lz in cell culture, suggesting that MLF and DnaJ-1 form a chaperone complex that directly regulates Lz activity. Importantly, dnaj-1 loss causes an increase in Lz+ blood cell number and size similarly as in mlf mutant larvae. Moreover we find that dnaj-1 genetically interacts with mlf to control Lz level and Lz+ blood cell development in vivo. In addition, we show that mlf and dnaj-1 loss alters Lz+ cell differentiation and that the increase in Lz+ blood cell number and size observed in these mutants is caused by an overactivation of the Notch signaling pathway. Finally, using different conditions to manipulate Lz activity, we show that high levels of Lz are required to repress Notch transcription and signaling. All together, our data indicate that the MLF/DnaJ-1-dependent increase in Lz level allows the repression of Notch expression and signaling to prevent aberrant blood cell development. Thus our findings establish a functional link between MLF and the co-chaperone DnaJ-1 to control RUNX transcription factor activity and Notch signaling during blood cell development in vivo.

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Section: Resultsmentioning

confidence: 99%

Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

et al. 2017

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“…Recently, we showed that Notch3 ECD accumulation in CADASIL occurs independently of ligand binding, suggesting that it may instead arise from a defect in Notch3 receptor trafficking. 28,29 In Drosophila , misregulation of endosomal trafficking of the Notch receptor had been linked to its aberrant activation 30 , a possibility that warrants investigation in CADASIL.…”

Section: Discussionmentioning

confidence: 99%

Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries

et al. 2017

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CADASIL, the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3R169C mouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone. In this study, we investigated the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3R169C mice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred prior to myogenic tone deficits. This defect was not prevented by genetic reduction of TIMP3 in TgNotch3R169C mice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3R170C/R170C) exhibited similar reductions in arterial lumen, and both TgNotch3R169C and Notch3R170C/R170C mice showed increased cerebral artery expression of Notch3 target genes. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3R169C mice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure-independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow.

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“…However, we could not confirm a transcriptional effect of Nef/NAKC via Notch1. A ligand-independent role of Notch1 is now recognized in endosomal trafficking (Palmer and Deng, 2015), shuttling surface proteins into endosomal compartments (Waters et al, 2012). Furthermore, the protein was found to be required for cytokine secretion in T cells (Benson et al, 2005, Manaster et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection

et al. 2016

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Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes. Key event was the Nef-mediated routing of the TNF-converting enzyme ADAM17 into Rab4 + early endosomes and the Rab27 + secretory pathway. Analysis of lymph-node tissue by multi-epitope-ligand-cartography (MELC) confirmed a vesicular TNF secretion phenotype that co-localized with persistent Nef expression, and implicated Notch1 as an essential co-factor. Surprisingly Notch1 had no transcriptional effect but was required for the endosomal trafficking of ADAM17. We conclude that Nef expression and Nef-containing pEV mobilize TNF from endosomal compartments in acute and chronic infection.

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Ligand-Independent Mechanisms of Notch Activity

Cited by 65 publications

References 89 publications

Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries

HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection

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