The AP-3 adaptor complex mediates sorting of yeast and mammalian PQ-loop-family basic amino acid transporters to the vacuolar/lysosomal membrane

Llinares, Elisa; Barry, Abdoulaye; André, Brunó

doi:10.1038/srep16665

Cited by 33 publications

(33 citation statements)

References 40 publications

(62 reference statements)

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“…This finding triggered the proposition of the so-called 'ALP pathway', in which Vps41 at the trans-Golgi regulates the formation of ALP-containing vesicles that traffic directly to the vacuole (Cowles et al, 1997a). Over the past few years, additional cargoes for the ALP pathway have been identified, which are all vacuolar membrane proteins (Llinares et al, 2015;Anand et al, 2009).…”

Section: Box 3 Insights From Yeastmentioning

confidence: 99%

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

Beek

Jonker

Welle

et al. 2019

Journal of Cell Science

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Multisubunit tethering complexes (MTCs) are multitasking hubs that form a link between membrane fusion, organelle motility and signaling. CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. They regulate the major membrane flows required for endocytosis, lysosome biogenesis, autophagy and phagocytosis. In addition, individual subunits control complex-independent transport of specific cargoes and exert functions beyond tethering, such as attachment to microtubules and SNARE activation. Mutations in CHEVI subunits lead to arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, while defects in CORVET and, particularly, HOPS are associated with neurodegeneration, pigmentation disorders, liver malfunction and various forms of cancer. Diseases and phenotypes, however, vary per affected subunit and a concise overview of MTC protein function and associated human pathologies is currently lacking. Here, we provide an integrated overview on the cellular functions and pathological defects associated with CORVET, CHEVI or HOPS proteins, both with regard to their complexes and as individual subunits. The combination of these data provides novel insights into how mutations in endo-lysosomal proteins lead to human pathologies.

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Section: Box 3 Insights From Yeastmentioning

confidence: 99%

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

Beek

Jonker

Welle

et al. 2019

Journal of Cell Science

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“…Biosynthetic vacuolar 55 cargoes initially move from the ER to the Golgi. Some vacuolar membrane proteins traffic directly 56 from the Golgi to the vacuole with the aid of the Golgi-associated AP-3 adaptor complex (Cowles 57 et al, 1997;Odorizzi et al, 1998;Llinares et al, 2015). By contrast, CPY and certain other 58 vacuolar hydrolases first traffic from the Golgi to PVE compartments (Vida et al, 1993;Conibear 59 and Stevens, 1998).…”

Section: Introductionmentioning

confidence: 99%

A microscopy-based kinetic analysis of yeast vacuolar protein sorting

Glick

Casler

2020

Preprint

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The yeast Saccharomyces cerevisiae is amenable to studying membrane traffic by live-cell 1 fluorescence microscopy. We used this system to explore two aspects of cargo protein traffic 2 through prevacuolar endosome (PVE) compartments to the vacuole. First, at what point during 3Golgi maturation does a biosynthetic vacuolar cargo depart from the maturing cisternae? To 4 address this question, we modified a regulatable fluorescent secretory cargo by adding a vacuolar 5 targeting signal. Traffic of the vacuolar cargo requires the GGA clathrin adaptors, which arrive 6 during the early-to-late Golgi transition. Accordingly, the vacuolar cargo begins to exit the Golgi 7 near the midpoint of maturation, significantly before exit of a secretory cargo. Second, how are 8 cargoes delivered from PVE compartments to the vacuole? To address this question, we tracked 9 biosynthetic and endocytic cargoes after they had accumulated in PVE compartments. The results 10 imply that stable PVE compartments repeatedly deliver material to the vacuole by a kiss-and-run 11 mechanism. 12

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“…Instead, we determined that both Pds1 and Esp1 are targeted to the vacuole using the ALP pathway. Although the ALP pathway is named because of the substrate initially described in this pathway (alkaline phosphatase), other proteins such as the vacuolar amino acid transporters Ypq1, Ypq2 and Ypq3 also require components of this pathway (45). We found that inhibition of the ALP pathway causes cells to adapt faster in response to a persistent DSB.…”

Section: Discussionmentioning

confidence: 83%

Yeast Securin is trafficked through the endomembrane system to regulate cell cycle arrest during the DNA damage response

Lemos¹,

Waterman²,

Haber³

2019

Preprint

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The yeast securin protein, Pds1, belongs to a class of highly conserved eukaryotic proteins that regulate the timing of chromatid segregation during mitosis by inhibiting separase, Esp1. During the metaphase to anaphase transition Pds1 is degraded by the ubiquitin-proteasome system in the nucleus, unleashing Esp1's protease activity to cleave cohesin surrounding sister chromatids. In response to DNA damage Pds1 is phosphorylated and stabilized, stalling mitotic progression to preserve genomic integrity. In addition, during the DNA damage checkpoint response, securin and separase are partially localized in the vacuole. Here we genetically dissect the requirements for securin's vacuolar localization and find that it is dependent on the Alkaline Phosphatase (ALP) endosomal transport pathway but not autophagy. Blocking retrograde traffic between the Golgi and the endoplasmic reticulum, by inhibiting COPI vesicle transport, drives Pds1 into the vacuole, whereas inhibiting antegrade transport by disrupting COPII-mediated traffic, results in the unexpected loss of Pds1 and the extinction of DNA damage-induced cell cycle arrest. We report that the induction of ER stress, either genetically or by treating cells with dithiothreitol, is sufficient to extinguish the DNA damage checkpoint, suggesting crosstalk between these two pathways. These data highlight new ways in which Pds1 and Esp1 are regulated during a DNA damage induced G2/M arrest and its requirement in the maintenance of the DNA damage checkpoint response.

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The AP-3 adaptor complex mediates sorting of yeast and mammalian PQ-loop-family basic amino acid transporters to the vacuolar/lysosomal membrane

Cited by 33 publications

References 40 publications

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

A microscopy-based kinetic analysis of yeast vacuolar protein sorting

Yeast Securin is trafficked through the endomembrane system to regulate cell cycle arrest during the DNA damage response

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