Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a conserved VSL region in Vta1

Azmi, Ishara F.; Davies, Brian A.; Dimaano, Christian; Payne, Johanna A.; Eckert, Debra M.; Babst, Markus; Katzmann, David J.

doi:10.1083/jcb.200508166

Cited by 139 publications

(274 citation statements)

References 26 publications

(87 reference statements)

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“…35 On the other hand, all of the ESCRT subunits remain tightly associated with the membrane in the absence of Vps4 (a multimeric AAA ATPase), thus blocking cargo sorting and generating an enlarged type of vesicles termed class E phenotype. 28,36 This result suggests that Vps4 activity is necessary for cargo transport and for removal of the ESCRT machinery from the endosomal membrane. However, even though dissociation of ESCRT-III is essential for sorting, it is not a prerequisite for luminal vesicle formation, 37 and for uncoupling MVB cargo sorting from the budding of vesicles into the endosomal lumen.…”

Section: Biogenesis Of Mvbsmentioning

confidence: 77%

Autophagy and multivesicular bodies: two closely related partners

2008

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In the majority of cell types, multivesicular bodies (MVBs) are a special kind of late endosomes, crucial intermediates in the internalization of nutrients, ligands and receptors through the endolysosomal system. ESCRT-0, I, II and III (endosomal sorting complex required for transport) are involved in the sorting of proteins into MVBs, generating the intraluminal vesicles. Autophagy is a lysosomal degradation pathway for cytoplasmic components such as proteins and organelles. The autophagosome, a well-characterized structure of the autophagy pathway, can fuse with endocytic structures such as MVBs to generate the amphisome. Finally, the amphisome fuses with the lysosome to degrade the material wrapped inside. Currently, clear evidence suggests that efficient autophagic degradation requires functional MVBs. This review highlights the most recent advances in our understanding of the molecular machinery that participates in MVB biogenesis and regulates the interplay between autophagy and this organelle.

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Section: Biogenesis Of Mvbsmentioning

confidence: 77%

Autophagy and multivesicular bodies: two closely related partners

2008

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“…Different MVB cargoes, such as Sna3 and Ste3 may be more sensitive to the level of ESCRT-I function, thereby revealing differential sorting phenotypes when ESCRT-I function is compromised by loss of Mvb12. However, in our experience GFP-CPS is the most sensitive cargo that can be used to address function of the MVB pathway (Azmi et al, 2006;our unpublished data). Thus, the observation that mvb12⌬ has only a subtle impact on the sorting of GFP-CPS seems to cast doubt upon this third model.…”

Section: Discussionmentioning

confidence: 99%

“…However, a large number of previously known vps mutants were identified, validating the experimental procedure (Supplemental Figure 1). In addition to previously known trafficking factors, this approach identified two mutants that displayed MVB sorting defects distinct from previously characterized class E vps mutants: vta1⌬ (Azmi et al, 2006) and deletion of YGR206w ( Figure 1 and Supplemental Figure 1). YGR206w encodes a 12-kDa protein that plays a role in MVB sorting and is referred to as MVB12.…”

Section: Identification Of Mvb12 As An Mvb Sorting Factormentioning

confidence: 99%

“…Pulse-chase analysis of CPS, carboxypeptidase Y (CPY), Sna3-GFP, and Sna3 KallR -GFP was performed as described previously (Babst et al, 2002a), and quantitation was performed using phosphorimaging screens and a Storm 840 system (GE Healthcare, Little Chalfont, Buckinghamshire, United Kingdom). Protein A purification using TAP-Mvb12 was performed as described in Azmi et al (2006), with the exception that 15 OD 600 of cells were lysed in phosphate-buffered saline. Proteins were visualized with polyclonal anti-Vps23 and anti-Vps28 (Katzmann et al, 2001).…”

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confidence: 99%

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Mvb12 Is a Novel Member of ESCRT-I Involved in Cargo Selection by the Multivesicular Body Pathway

Oestreich

Davies

Payne

et al. 2007

MBoC

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The multivesicular body (MVB) sorting pathway impacts a variety of cellular functions in eukaryotic cells. Perhaps the best understood role for the MVB pathway is the degradation of transmembrane proteins within the lysosome. Regulation of cargo selection by this pathway is critically important for normal cell physiology, and recent advances in our understanding of this process have highlighted the endosomal sorting complexes required for transport (ESCRTs) as pivotal players in this reaction. To better understand the mechanisms of cargo selection during MVB sorting, we performed a genetic screen to identify novel factors required for cargo-specific selection by this pathway and identified the Mvb12 protein. Loss of Mvb12 function results in differential defects in the selection of MVB cargoes. A variety of analyses indicate that Mvb12 is a stable member of ESCRT-I, a heterologous complex involved in cargo selection by the MVB pathway. Phenotypes displayed upon loss of Mvb12 are distinct from those displayed by the previously described ESCRT-I subunits (vacuolar protein sorting 23, -28, and -37), suggesting a distinct function than these core subunits. These data support a model in which Mvb12 impacts the selection of MVB cargoes by modulating the cargo recognition capabilities of ESCRT-I. INTRODUCTIONThe endosomal system coordinates protein trafficking between various subcellular compartments, including the Golgi, plasma membrane, and lysosome. Cell surface proteins, including activated receptors, that have undergone endocytosis are typically recycled to the plasma membrane or targeted deeper into the endosomal pathway for degradation within the lysosome. Endosomal membrane proteins destined for the lumen of the lysosome undergo an additional sorting reaction during their inclusion into the multivesicular body (MVB) pathway (for review, see Gruenberg and Stenmark, 2004;Babst, 2005). MVBs form when the limiting membrane of the late endosome invaginates and buds into the lumen of the organelle, actively selecting a subset of the proteins from the limiting membrane in the process (Gorden et al., 1978;Haigler et al., 1979). The intralumenal vesicles within the MVB and their contents are exposed to hydrolases within the lysosome as a consequence of heterotypic fusion of these organelles. By contrast, proteins within the limiting membrane of the MVB are delivered to the limiting membrane of the lysosome/vacuole after heterotypic fusion (Odorizzi et al., 1998).Sorting of cargo into the MVB pathway and heterotypic fusion with the lysosme/vacuole leads to delivery into the hydrolytic lumen of the organelle, and therefore entry into this pathway must be highly regulated. Ubiquitination is the best-characterized cis-acting signal mediating entry into the MVB pathway (for reviews, see Katzmann et al., 2002;Hicke and Dunn, 2003;Raiborg et al., 2003). Studies in organisms ranging from the yeast Saccharomyces cerevisiae, to mammalian cells have demonstrated that ubiquitin modification of a variety of MVB cargoes is a requisit...

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“…We found that mutation of either VPS68 or VPS55 similarly slows the transit of biosynthetic and endocytic cargo proteins through the MVB, but does not block the formation of intralumenal vesicles or cause the accumulation of an aberrant protease-active compartment. A subset of class E vps mutants (including did2/fti1/vps46, vps60, and vta1) that affect ESCRT function by regulating the AAA ATPase Vps4p exhibit mild CPY-sorting defects (Ͻ20%) and partial impairment of lumenal MVB vesicle formation (Azmi et al, 2006;Lottridge et al, 2006). Our results do not preclude a similar role for the Vps55/68 complex in regulating ESCRT proteins and increasing the efficiency of lumenal vesicle formation; however, the strong CPY-sorting defects of vps55 and vps68 mutants suggest they have a different function.…”

Section: The Vps55/68 Complex Is Required For Two Transport Steps Outmentioning

confidence: 99%

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

Schluter

Lam

Brumm

et al. 2008

MBoC

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Endosomal transport is critical for cellular processes ranging from receptor down-regulation and retroviral budding to the immune response. A full understanding of endosome sorting requires a comprehensive picture of the multiprotein complexes that orchestrate vesicle formation and fusion. Here, we use unsupervised, large-scale phenotypic analysis and a novel computational approach for the global identification of endosomal transport factors. This technique effectively identifies components of known and novel protein assemblies. We report the characterization of a previously undescribed endosome sorting complex that contains two well-conserved proteins with four predicted membrane-spanning domains. Vps55p and Vps68p form a complex that acts with or downstream of ESCRT function to regulate endosomal trafficking. Loss of Vps68p disrupts recycling to the TGN as well as onward trafficking to the vacuole without preventing the formation of lumenal vesicles within the MVB. Our results suggest the Vps55/68 complex mediates a novel, conserved step in the endosomal maturation process. INTRODUCTIONEndosomal protein sorting is a highly conserved cellular process that is required for receptor down-regulation, viral replication, and development (Katzmann et al., 2002;Morita and Sundquist, 2004). Much progress has been made in recent years in identifying distinct multiprotein complexes that regulate the fusion of primary endocytic vesicles, the maturation of an early endosome into a multivesicular body (MVB), and the recycling of proteins and lipids to other organelles (Gruenberg and Stenmark, 2004;Bonifacino and Rojas, 2006). The ESCRT-I, -II, and -III complexes (endosomal-sorting complex required for transport), which act in sequence to regulate the formation of internal vesicles at the MVB, play a central role in endosome biogenesis (Katzmann et al., 2002;Hurley and Emr, 2006). Other transport complexes regulate the targeting and fusion of endosomes or endosome-derived vesicles with other organelles (Bowers and Stevens, 2005;Bonifacino and Rojas, 2006).Many components of the endosomal-sorting machinery were first identified in yeast genetic screens for mutants that are defective in protein transport to the yeast vacuole, which requires functional endosomal sorting and recycling (Bowers and Stevens, 2005). Most of these components have a conserved role in endosome biogenesis in higher cells. Mammalian homologues have been identified for most if not all yeast ESCRT subunits (von Schwedler et al., 2003;Hurley and Emr, 2006), and at least some of the machinery that regulates recycling from the MVB is also well conserved. For example, the five-subunit retromer complex that mediates endosome-to-trans-Golgi network (TGN) transport in yeast is associated with tubular regions of the endosome in mammalian cells and mediates retrograde transport (Arighi et al., 2004;Seaman, 2004). In the past 20 years, classical genetic screens have identified more than 50 vacuole protein-sorting (VPS) genes (Bowers and Stevens, 2005). Surprisingly, ...

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Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a conserved VSL region in Vta1

Cited by 139 publications

References 26 publications

Autophagy and multivesicular bodies: two closely related partners

Autophagy and multivesicular bodies: two closely related partners

Mvb12 Is a Novel Member of ESCRT-I Involved in Cargo Selection by the Multivesicular Body Pathway

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

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