Molecular Architecture and Functional Model of the Complete Yeast ESCRT-I Heterotetramer

Kostelansky, M.S.; Schluter, Cayetana; Tam, Yun K.; Lee, Sangho; Ghirlando, Rodolfo; Beach, Bridgette M.; Conibear, Elizabeth; Hurley, James H.

doi:10.1016/j.cell.2007.03.016

Cited by 165 publications

(248 citation statements)

References 44 publications

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“…This cluster, which contains 18 genes that encode all 13 nonredundant V-ATPase subunits, 2 overlapping ORFs, and 3 dedicated V-ATPase assembly factors, lacks only VPH1 and STV1, which encode two isoforms of the 100-kDa stator subunit with partially overlapping functions. The secondlargest cluster contains 13 genes corresponding to all known components of ESCRT-I, -II, and -III complexes apart from the newly described ESCRT-I subunit Mvb12 (Chu et al, 2006;Curtiss et al, 2007;Kostelansky et al, 2007;Oestreich et al, 2007) and also includes the ESCRT-associated factors Vps27p, Vps4p, and Bro1p (Bowers and Stevens, 2005). The fact that all three ESCRT subcomplexes were found in a single cluster is consistent with their highly interdependent function in MVB formation.…”

Section: Identification Of New and Known Complexesmentioning

confidence: 55%

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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Section: Identification Of New and Known Complexesmentioning

confidence: 55%

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

Schluter

Lam

Brumm

et al. 2008

MBoC

Self Cite

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“…The ESCRT machinery, which is formed by four ESCRT proteins (ESCRT‐0, ESCRT‐I, ESCRT‐II, and ESCRT‐III) and accessory proteins including ALIX and VPS4, assemble components of Exos together by forming intraluminal vesicles 60. ESCRT‐I is a claviform heterotetramer of tumor susceptibility gene 101, vacuolar protein sorting‐associated protein 28 (VPS28), the VPS37 Homolog (VPS37A/B/C/D), and one of the multivesicular body subunit 12A (MVB12A), MVB12B, or ubiquitin‐associated protein 1 61, 62. ESCRT‐II is a bifurcate heterotetramer consisting of one molecule each of VPS22 and VPS36 and two molecules of VPS25 63, 64, 65.…”

Section: Biogenesis and Release Of Evsmentioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native‐source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the “modular design” of EV components. One high‐yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized “modular design” components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine.

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“…During endosomal maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are then delivered to lysosomes for degradation 1,2 . It is well known that cargo molecules such as epidermal growth factor (EGF) receptor are ubiquitinated and sorted into ILVs, which is destined for lysosomal degradation, in an endosomalsorting complex required for transport (ESCRT) machinerydependent manner [3][4][5][6][7][8][9][10][11][12][13][14][15][16] . In this system, a phospholipid metabolite, lysobisphoshatidic acid, has also been shown to have a role in ILV formation 17 .…”

mentioning

confidence: 99%

Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

et al. 2013

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During late endosome maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are either delivered to lysosomes for degradation or fused with the plasma membranes for exosome release. The mechanism underlying formation of exosomal ILVs and cargo sorting into ILVs destined for exosome release is still unclear. Here we show that inhibitory G protein (Gi)-coupled sphingosine 1-phosphate (S1P) receptors regulate exosomal MVE maturation. Gi-coupled S1P receptors on MVEs are constitutively activated through a constant supply of S1P via autocrine activation within organelles. We also found that the continuous activation of Gi-coupled S1P receptors on MVEs is essential for cargo sorting into ILVs destined for exosome release. Our results reveal a mechanism underlying ESCRT-independent maturation of exosomal MVEs.

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Molecular Architecture and Functional Model of the Complete Yeast ESCRT-I Heterotetramer

Cited by 165 publications

References 44 publications

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

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

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

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