Dataset Information

Scube2 primes Dispatched and ADAM10-mediated Shh release by recruiting HDL acceptors to the plasma membrane

ABSTRACT: Sonic hedgehog (Shh) morphogens are lipidated proteins that firmly attach to the outer plasma membrane (PM) of the cells that produce them. The process by which Shh is solubilized includes the transmembrane protein Dispatched1 (Disp), the soluble glycoprotein Scube2, the proteolytic removal of lipidated peptide termini, and the use of soluble lipoproteins (LPPs) as Shh transporters. However, their molecular interplay remains controversial. Here, we demonstrate that A Disintegrin and Metalloproteinase 10, Scube2, and Disp act synergistically to remove Shh from the PM and transfer it to LPP acceptors. We also demonstrate physical Scube2 interactions with LPPs and that these interactions increase Shh release. Finally, we demonstrate that Scube2 strongly binds to heparan sulfate (HS) on cell surfaces. These findings reveal Scube2’s previously unknown role in binding low-abundance, soluble LPP carriers for Shh and recruiting these carriers to HS-rich Shh release sites at the PM to enhance morphogen release.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Janna Puschmann

LAB HEAD: Kay Grobe

PROVIDER: PXD071371 | Pride | 2026-02-23

REPOSITORIES: Pride

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Scube2 primes Dispatched and ADAM10-mediated Shh release by recruiting HDL acceptors to the plasma membrane.

Puschmann J J Steffes G G Froese J J Manikowski D D Ehring K K Wittke J J Garbers C C Wegner S V SV Grobe K K

Communications biology 20260108 1

Sonic hedgehog (Shh) morphogens are lipidated proteins that firmly attach to the outer plasma membrane (PM) of the cells that produce them. The process by which Shh is solubilized requires the transmembrane protein Dispatched1 (Disp), the soluble glycoprotein Scube2, the proteolytic removal of lipidated peptide termini, and the use of soluble lipoproteins (LPPs) as Shh transporters. However, their molecular interplay remains controversial. Here, we demonstrate that A Disintegrin and Metalloprote ...[more]

PMID: 41507312

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Project description:Zinc (Zn) is a major elemental component of respirable ambient particulate matter (PM) detected often at alarming levels in urban air. Exposure to PM has been widely associated with increased cardiovascular morbidity and mortality, however, it is not known what components or sources of PM are causative. We recently demonstrated that long-term episodic inhalation of combustion PM, having similar amount of Zn found in urban PM, caused myocardial lesions in rats. We further demonstrated that a single pulmonary exposure to Zn at high concentration is associated with disturbances in cardiac mitochondrial function, ion channel regulation, calcium homeostasis, and cell signaling. Therefore, in this study we investigated the role of PM-associated Zn in cardiac injury using multiple exposure scenarios. Male Wistar-Kyoto (WKY) rats of 12-14 wks age were intratracheally exposed (once per wk x 8 or16 wks) to either (1) saline (control); (2) PM having no soluble Zn; (3) combustion PM suspension containing 14.5 ug/mg water-soluble Zn at high and (4) low dose levels, (5) the aqueous fraction of this suspension devoid of solid insoluble particulate fraction (14.5 ug/mg soluble Zn), or (6) Zn sulfate. Zn concentrations were identical in groups 3, 5 and 6. Pulmonary toxicity was apparent in all exposure groups when compared to saline as determined by recovery of cells in bronchoalveolar lavage fluid. Long-term exposure to PM with or without soluble Zn, or Zn sulfate caused distinct myocardial lesions characterized by subepicardial and randomly distributed myocardial inflammation, degeneration, and fibrosis. The lesion severity was higher in those groups receiving Zn PM. Because cardiac mitochondria are likely the primary target of inhaled metal or other absorbed PM components, we analyzed mitochondrial DNA damage using QPCR and found that all exposure groups except those exposed to PM without Zn caused variable degree of damage. Aconitase activity, sensitive to inhibition by oxidative stress was inhibited slightly but significantly in rats receiving zinc sulfate. Although modest, microarray (Affymetrix) analysis revealed expression changes in the heart reflective of effects on cell signaling, inflammation/oxidative stress, mitochondrial fatty acid metabolisms and cell cycle regulation in rats exposed to zinc sulfate. However, these changes were minimal following exposure to PM devoid of soluble metals. We demonstrate that episodic subchronic pulmonary exposure to zinc sulfate causes cardiac injury and mitochondrial DNA damage. Thus, water-soluble PM-associated zinc may be one of the PM components responsible for cardiovascular morbidity. Experiment Overall Design: Group 1 received Saline to serve as a control. Group 2 received Mount St. Helenâs ash, which does not contain any water-soluble zinc or other metals such that we can delineate any cardiac effect secondary to pulmonary deposition of these particles as these fine mode particles themselves are not likely to translocate to the heart. Group 3 received whole saline suspension of the same fugitive oil combustion particle sample used in the previous study, which contained insoluble components plus water-soluble zinc (Kodavanti et al., 2003; 14.5 ug/mg zinc) and also a small amount of water-soluble nickel (3.0 Âµg/mg). Elemental composition of this PM is comparable to Ottawa urban PM (Kodavanti et al., 2003). Group 4 also received same particle sample but at half the dose than group 3. Group 5 received saline-soluble or leachable fraction of PM-HD devoid of any solid material but contained soluble components including zinc and nickel. And, group 6 received zinc sulfate at concentration that was present in groups 3 or 5. This design allowed us to test if cardiac injury in rats was due to leached of zinc or solid particles. There were 4 replicates per treatment group.

Project description:Zinc (Zn) is a major elemental component of respirable ambient particulate matter (PM) detected often at alarming levels in urban air. Exposure to PM has been widely associated with increased cardiovascular morbidity and mortality, however, it is not known what components or sources of PM are causative. We recently demonstrated that long-term episodic inhalation of combustion PM, having similar amount of Zn found in urban PM, caused myocardial lesions in rats. We further demonstrated that a single pulmonary exposure to Zn at high concentration is associated with disturbances in cardiac mitochondrial function, ion channel regulation, calcium homeostasis, and cell signaling. Therefore, in this study we investigated the role of PM-associated Zn in cardiac injury using multiple exposure scenarios. Male Wistar-Kyoto (WKY) rats of 12-14 wks age were intratracheally exposed (once per wk x 8 or16 wks) to either (1) saline (control); (2) PM having no soluble Zn; (3) combustion PM suspension containing 14.5 ug/mg water-soluble Zn at high and (4) low dose levels, (5) the aqueous fraction of this suspension devoid of solid insoluble particulate fraction (14.5 ug/mg soluble Zn), or (6) Zn sulfate. Zn concentrations were identical in groups 3, 5 and 6. Pulmonary toxicity was apparent in all exposure groups when compared to saline as determined by recovery of cells in bronchoalveolar lavage fluid. Long-term exposure to PM with or without soluble Zn, or Zn sulfate caused distinct myocardial lesions characterized by subepicardial and randomly distributed myocardial inflammation, degeneration, and fibrosis. The lesion severity was higher in those groups receiving Zn PM. Because cardiac mitochondria are likely the primary target of inhaled metal or other absorbed PM components, we analyzed mitochondrial DNA damage using QPCR and found that all exposure groups except those exposed to PM without Zn caused variable degree of damage. Aconitase activity, sensitive to inhibition by oxidative stress was inhibited slightly but significantly in rats receiving zinc sulfate. Although modest, microarray (Affymetrix) analysis revealed expression changes in the heart reflective of effects on cell signaling, inflammation/oxidative stress, mitochondrial fatty acid metabolisms and cell cycle regulation in rats exposed to zinc sulfate. However, these changes were minimal following exposure to PM devoid of soluble metals. We demonstrate that episodic subchronic pulmonary exposure to zinc sulfate causes cardiac injury and mitochondrial DNA damage. Thus, water-soluble PM-associated zinc may be one of the PM components responsible for cardiovascular morbidity. Keywords: Pulmonary exposure, Cardiac gene expression

			Action	DRS
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	3375_IDmapping.fasta	Fasta
	E3_3375_01.raw	Raw
	E3_3375_02.raw	Raw
	E3_3375_03.raw	Raw