Dataset Information

The ER-embedded UBE2J1/RNF26 ubiquitylation complex in spatio-temporal control of the endolysosomal pathwayThe ER-embedded UBE2J1/RNF26 ubiquitylation complex in spatio-temporal control of the endolysosomal pathway

ABSTRACT: The endolysosomal system fulfills a wide variety of cellular functions, many of which are modulated through interactions with other organelles. In particular, the ER exerts spatiotemporal constraints on the organization and motility of endosomes and lysosomes. We have recently described the ER transmembrane E3 ubiquitin ligase RNF26 as a regulator of perinuclear positioning and transport dynamics of the endolysosomal network. We now report that the ubiquitin conjugating enzyme UBE2J1, also anchored in the ER membrane, collaborates with RNF26 in this context, and that the cellular activity of this E2/E3 pair, localized in a perinuclear ER subdomain, is supported by transmembrane interactions. Through modification of SQSTM1/p62 on lysine 435, the ER-embedded UBE2J1/RNF26 ubiquitylation complex recruits endosomal adaptors to immobilize their cognate vesicles in the perinuclear region of the cell. The resulting spatiotemporal compartmentalization of the endolysosomal system promotes trafficking of activated EGFR to the late compartments and facilitates cessation of downstream AKT signaling.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Fredrik Trulsson

LAB HEAD: Alfred Vertegaal

PROVIDER: PXD022104 | Pride | 2021-01-22

REPOSITORIES: Pride

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The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal control over the endolysosomal pathway.

Cremer Tom T Jongsma Marlieke L M MLM Trulsson Fredrik F Vertegaal Alfred C O ACO Neefjes Jacques J Berlin Ilana I

Cell reports 20210101 3

The endolysosomal system fulfills a wide variety of cellular functions, many of which are modulated through interactions with other organelles. In particular, the ER exerts spatiotemporal constraints on the organization and motility of endosomes and lysosomes. We have recently described the ER transmembrane E3 ubiquitin ligase RNF26 as a regulator of endolysosomal perinuclear positioning and transport dynamics. Here, we report that the ubiquitin conjugating enzyme UBE2J1, also anchored in the ER ...[more]

PMID: 33472082

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Project description:The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide novel insights into NVU formation and function and offer new avenues for investigating diseases involving white matter defects and vascular abnormalities. The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide novel insights into NVU formation and function and offer new avenues for investigating diseases involving white matter defects and vascular abnormalities. The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide novel insights into NVU formation and function and offer new avenues for investigating diseases involving white matter defects and vascular abnormalities.

			Action	DRS
	2xHA_P62.fasta	Fasta
	EV_1.raw	Raw
	EV_2.raw	Raw
	EV_3.raw	Raw
	GlyGlyKSites.txt	Txt