The Yeast Alix Homolog Bro1 Functions as a Ubiquitin Receptor for Protein Sorting into Multivesicular Endosomes

Pashkova, Natasha; Gakhar, Lokesh; Winistorfer, Stanley C.; Sunshine, Anna B.; Rich, Matthew S.; Dunham, Maitreya J.; Yu, Liping; Piper, Robert C.

doi:10.1016/j.devcel.2013.04.007

Cited by 90 publications

(126 citation statements)

References 60 publications

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“…These include Tom1, Tom1L1, and GGA3, which bind clathrin, Ub, and ESCRT-I supporting the idea that several ESCRT-0-like complexes gather Ub cargo and pass it to a central ESCRT-I/-II supercomplex (Shields and Piper 2011;Haglund and Dikic 2012). Recently, other contenders for Ub-sorting receptors have been identified including Bro1, Alix, and HD-PTP, which bind Ub, and interact with ESCRT-I and ESCRT-III (Ali et al 2013;Pashkova et al 2013). These proteins could potentially offer an additional sorting pathway for Ub cargo in parallel with ESCRT-0.…”

Section: Sequential Orchestration Of Escrt Functionmentioning

confidence: 84%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

193

176

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When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. HOW PROTEINS ARE SELECTED FOR UBIQUITINATIONU biquitin (Ub) is covalently attached to substrate proteins by the concerted action of E2-conjugating enzymes and E3 ligases (Varshavsky 2012). Most of the specificity and regulation of ubiquitination is at the level of the E3 ligases, which vastly outnumber the E2-conjugating enzymes. Ubiquitination results from the transfer of Ub, held either by the E2 or in some cases by the E3 as a high-energy thioester bond, onto a substrate protein, typically on the terminal amide of a substrate acceptor lysine side chain. Owing to the intense interest in the ubiquitination system, many of the simple rules and distinctions concerning different types of ligases, their specificity for forming particular polyUb chains, and even the kinds of residues in substrate proteins that can be ubiquitin modified, have been blurred with the discovery of mixed poly-Ub chains, new enzymatic mechanisms for Ub transfer, and ubiquitination of nonlysine residues (Kulathu and Komander 2012;Wenzel and Klevit 2012;McDowell and Philpott 2013). Nonetheless, in basic terms, Ub ligases function as platforms that coordinate substrate recognition with Ub transfer as well as configuring poly-Ub chain topology by the E2-conjugating enzyme. Substrates can be bound directly by the E3 ligase or by adaptor proteins that in turn bind to ligases, and selecEditors:

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Section: Sequential Orchestration Of Escrt Functionmentioning

confidence: 84%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

193

176

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“…Specifically, nonuniquely mapping reads, reads in which the pair did not map, reads with a mapping quality <30, and PCR/optical duplicate reads were filtered out; the samtools C‐50 filter was applied as recommended for reads mapped with BWA and the vcfutils.pl varFilter ‐D filter was applied with D set to 2X the average mapping coverage. SNVs unique to the evolved clones were identified with a custom Python script, annotated with a second Python script (http://depts.washington.edu/sfields/software/annotate/) (Pashkova et al ., 2013) and further prioritized by manual examination with the Integrative Genome Viewer (IGV) (Robinson et al ., 2011). …”

Section: Methodsmentioning

confidence: 99%

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

et al. 2016

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SummaryAneuploidy and aging are correlated; however, a causal link between these two phenomena has remained elusive. Here, we show that yeast disomic for a single native yeast chromosome generally have a decreased replicative lifespan. In addition, the extent of this lifespan deficit correlates with the size of the extra chromosome. We identified a mutation in BUL1 that rescues both the lifespan deficit and a protein trafficking defect in yeast disomic for chromosome 5. Bul1 is an E4 ubiquitin ligase adaptor involved in a protein quality control pathway that targets membrane proteins for endocytosis and destruction in the lysosomal vacuole, thereby maintaining protein homeostasis. Concurrent suppression of the aging and trafficking phenotypes suggests that disrupted membrane protein homeostasis in aneuploid yeast may contribute to their accelerated aging. The data reported here demonstrate that aneuploidy can impair protein homeostasis, shorten lifespan, and may contribute to age‐associated phenotypes.

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“…Bro1p (ALIX in mammals) is known to bind to ubiquitinated cargo proteins in the endosome and recruits ESCRT-III factors to facilitate formation of ILVs in the late endosomes as well as HIV budding out of the infected cells (57)(58)(59). ALIX is also involved in maintaining phosphate homeostasis in plants through mediating trafficking of a phosphate transporter in plants (60).…”

mentioning

confidence: 99%

Role of Viral RNA and Co-opted Cellular ESCRT-I and ESCRT-III Factors in Formation of Tombusvirus Spherules Harboring the Tombusvirus Replicase

Kovalev

Martín

Pogany

et al. 2016

J Virol

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Plus-stranded RNA viruses induce membrane deformations in infected cells in order to build viral replication complexes (VRCs).One of the intriguing aspects of VRC formation is the need for extensive subcellular membrane deformations. Accordingly, (ϩ)RNA viruses replicate in various membranous structures that could be formed from various membranes, such as endoplasmic reticulum, mitochondria, endosome, chloroplast, peroxisome, and plasma membranes, or induced de novo (1,(3)(4)(5). Membrane deformations are possibly induced by co-opted cellular phospholipid kinases, local enrichment of sterols, and subverted membrane-bending proteins, such as ESCRT factors, reticulons, and amphiphysins (6-12).A major type of subcellular membrane deformation induced by some (ϩ)RNA viruses is represented by vesicle-like small invaginations with single narrow openings toward the cytosol (13,14). These structures, called spherules, contain the membranebound VRCs consisting of viral and co-opted cellular proteins in the infected cells (1)(2)(3)(15)(16)(17)(18). The membranous spherule structures sequester all the replication factors into a confined cytosolic area and likely protect the fragile viral (ϩ)RNA from degradation

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The Yeast Alix Homolog Bro1 Functions as a Ubiquitin Receptor for Protein Sorting into Multivesicular Endosomes

Cited by 90 publications

References 60 publications

Ubiquitin-Dependent Sorting in Endocytosis

Ubiquitin-Dependent Sorting in Endocytosis

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

Role of Viral RNA and Co-opted Cellular ESCRT-I and ESCRT-III Factors in Formation of Tombusvirus Spherules Harboring the Tombusvirus Replicase

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