The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development

Messler, Sabine; Kropp, Sonja; Episkopou, Vasso; Felici, Angelina; Würthner, Jan; Lemke, Robin; Jerabek‐Willemsen, Moran; Willecke, Regina; Scheu, Stefanie; Pfeffer, Klaus

doi:10.1016/j.imbio.2010.07.006

Cited by 28 publications

(32 citation statements)

References 41 publications

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“…TGFBRAP1 to VPS39 exchange might further be regulated by proteins such as MON1-CCZ1 (Fig. 6B), which are recruited by CORVET, interact with VPS39, and act as activators of RAB7 (44 -46) and signaling pathways such as the TGF␤ pathway, which has been shown to intersect with TGFBRAP1 and VPS39 function (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

Kant

Jonker

Wijdeven

et al. 2015

Journal of Biological Chemistry

117

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Background:The CORVET and HOPS complexes regulate endosomal cargo trafficking but have not been well characterized in mammals. Results: A detailed analysis of subunit interactions within the mammalian CORVET, HOPS, and VIPAS39/VPS33B complexes. Conclusion: Tethering complexes have adapted to the higher complexity of trafficking in mammalian cells. Significance: This work provides a detailed architectural insight into the mammalian endosomal tethering complexes.

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Section: Discussionmentioning

confidence: 99%

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

Kant

Jonker

Wijdeven

et al. 2015

Journal of Biological Chemistry

117

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“…Defects in HOPS or CORVET subunits in mammalian tissues result in strong deficiencies. For instance, loss of hVps39-1 (TLP), the homologous hVps39-2 (TRAP-1), hVps41 (hVam2) or hRab7 results in embryonic lethality as early as gastrulation Kawamura et al, 2012;Messler et al, 2011) and also causes extensive developmental defects in zebrafish (Schonthaler et al, 2008). Likewise, mutants in HOPS impair infection by Ebola virus (Carette et al, 2011) and export of HIV virions (Tomita et al, 2011), affect endosomal, phagosomal and lysosomal biogenesis (Caplan et al, 2001;Poupon et al, 2003;Pols et al, 2012;Sriram et al, 2003;Swetha et al, 2011;Kinchen et al, 2008) and, subsequently, development (Wilkin et al, 2008).…”

Section: Functions Of Hops and Corvet Beyond Yeastmentioning

confidence: 99%

“…Mutations in Vps33B and Vps16B, which could be part of the metazoan CORVET, are further linked to diseases such as arthrogryposisrenal-dysfunction-cholestasis (ARC) syndrome, an autosomal recessive disorder, and cancer (Gissen et al, 2004;Roy et al, 2011). Several of the observed defects are likely to be associated with defective signaling through the endosome, which impairs morphogen gradients, receptor degradation and subsequently affects embryonic development or causes strong developmental defects within the entire organism (Charng et al, 1998;Wurthner et al, 2001;Felici et al, 2001;Aoyama et al, 2012;Kawamura et al, 2012;Messler et al, 2011;Wilkin et al, 2008). Data from localizing hVps39-1 and hVps41 as well as other class C proteins in mammalian cells are consistent with the observations in yeast that HOPS is involved in endosome-lysosome fusion (Caplan et al, 2001;Pols et al, 2012).…”

Section: Functions Of Hops and Corvet Beyond Yeastmentioning

confidence: 99%

CORVET and HOPS tethering complexes–coordinators of endosome and lysosome fusion

Balderhaar

Ungermann

2013

Journal of Cell Science

460

470

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SummaryProtein and lipid transport along the endolysosomal system of eukaryotic cells depends on multiple fusion and fission events. Over the past few years, the molecular constituents of both fission and fusion machineries have been identified. Here, we focus on the mechanism of membrane fusion at endosomes, vacuoles and lysosomes, and in particular on the role of the two homologous tethering complexes called CORVET and HOPS. Both complexes are heterohexamers; they share four subunits, interact with Rab GTPases and soluble NSF attachment protein receptors (SNAREs) and can tether membranes. Owing to the presence of specific subunits, CORVET is a Rab5 effector complex, whereas HOPS can bind efficiently to late endosomes and lysosomes through Rab7. Based on the recently described overall structure of the HOPS complex and a number of in vivo and in vitro analyses, important insights into their function have been obtained. Here, we discuss the general function of both complexes in yeast and in metazoan cells in the context of endosomal biogenesis and maturation.

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“…9,[14][15][16] In higher eukaryotes, HOPS subunits have been characterized, implicating a similar function as in yeast. [17][18][19][20][21][22][23][24][25][26][27][28] Due to the exogenous expression and the presence of multiple isoforms for some of the identified HOPS subunits it remains unclear if HOPS or CORVET is analyzed in some studies. The core subunits Vps18 and Vps11 have one clear homolog in mammalian cells and Vps16 and Vps33 are both expressed as an A and B isoform.…”

Section: Introductionmentioning

confidence: 99%

“…24,27 Vps39 has 2 homologs: Vps39-1/ hVam6/TLP and Vps39-2/TRAP1. 21,32,33 Since the hVps39 proteins are also homologous to yeast Vps3, it was proposed that one of them is the missing metazoan Vps3 and part of the mammalian CORVET complex. 34,35 Here, we characterized the human Vps39 homologs in yeast and in HEK293 cells and found that the 2 isoforms cannot compensate for a loss of yeast Vps39.…”

Section: Introductionmentioning

confidence: 99%

The Vps39-like TRAP1 is an effector of Rab5 and likely the missing Vps3 subunit of human CORVET

et al. 2014

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Membrane fusion in the endocytic pathway is mediated by a protein machinery consistent of Rab GTPases, tethering factors and SNAREs. In yeast, the endosomal CORVET and lysosomal HOPS tethering complexes share 4 of their 6 subunits. The 2 additional subunits in each complex -Vps3 and Vps8 for CORVET, and the homologous Vps39 and Vps41 for HOPS -bind directly to Rab5 and Rab7, respectively. In humans, all subunits for HOPS have been described. However, human CORVET remains poorly characterized and a homolog of Vps3 is still missing. Here we characterize 2 previously identified Vps39 isoforms, hVps39-1/hVam6/TLP and hVps39-2/TRAP1, in yeast and HEK293 cells. None of them can compensate the loss of the endogenous yeast Vps39, though the specific interaction of hVps39-1 with the virus-specific LT protein was reproduced. Both human Vps39 proteins show a cytosolic localization in yeast and mammalian cells. However, hVps39-2/TRAP1 strongly co-localizes with co-expressed Rab5 and interacts directly with Rab5-GTP in vitro. We conclude that hVps39-2/TRAP1 is an endosomal protein and an effector of Rab5, suggesting a role of the protein as a subunit of the putative human CORVET complex.

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The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development

Cited by 28 publications

References 41 publications

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

CORVET and HOPS tethering complexes–coordinators of endosome and lysosome fusion

The Vps39-like TRAP1 is an effector of Rab5 and likely the missing Vps3 subunit of human CORVET

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