<i>Caenorhabditis elegans</i>HOPS and CCZ-1 mediate trafficking to lysosome-related organelles independently of RAB-7 and SAND-1

Delahaye, Jared L.; Foster, Olivia K.; Vine, Annalise; Saxton, Daniel S; Curtin, Thomas P.; Somhegyi, Hannah; Salesky, Rebecca; Hermann, Greg J.

doi:10.1091/mbc.e13-09-0521

Cited by 20 publications

(53 citation statements)

References 149 publications

(224 reference statements)

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“…Formation of lysosome-related organelles (LROs) has many mechanistic commonalities with that of conventional lysosomes, although with some molecular differences [53–55], and also requires the HOPS complex [18,53,56,57]. Mutations in Drosophila HOPS components disrupt the formation of the pigment granule, an insect LRO, leading to a loss of eye coloration [30,58–63].…”

Section: Resultsmentioning

confidence: 99%

“…A LE-centric role of Rab2 in the endolysosomal pathway also explains why we do not detect any obvious perturbation of LRO formation in Rab2 null flies. Although the LRO biogenesis pathway in many aspects resembles that of conventional lysosomes, there is evidence suggesting that, at least for some types of LROs, it bypasses the LE compartment [53]. …”

Section: Discussionmentioning

confidence: 99%

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Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

2018

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Rab2 is a conserved Rab GTPase with a well-established role in secretory pathway function and phagocytosis. Here we demonstrate that Drosophila Rab2 is recruited to late endosomal membranes, where it controls the fusion of LAMP-containing biosynthetic carriers and lysosomes to late endosomes. In contrast, the lysosomal GTPase Gie/Arl8 is only required for late endosome-lysosome fusion, but not for the delivery of LAMP to the endocytic pathway. We also find that Rab2 is required for the fusion of autophagosomes to the endolysosomal pathway, but not for the biogenesis of lysosome-related organelles. Surprisingly, Rab2 does not rely on HOPS-mediated vesicular fusion for recruitment to late endosomal membranes. Our work suggests that Drosophila Rab2 is a central regulator of the endolysosomal and macroautophagic/autophagic pathways by controlling the major heterotypic fusion processes at the late endosome.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

2018

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“…In addition, yeast Vps39p has been reported to act independently of the remainder of the HOPS complex in creating contact sites between vacuoles and mitochondria and it is also proposed to play a role in controlling the activity of target of rapamycin complex 1 (TORC1) . Very little is known about how the metazoan HOPS complex functions at the mechanistic level, although functionally some or all HOPS proteins have been shown to be required for the maturation of endosomes , homotypic fusion of late endosomes , the delivery of endocytosed cargo to lysosomes , the biogenesis of lysosome related organelles [LROs; ], Ebola virus entry into cultured cells , the resistance of melanoma cells to cytotoxic agents , the fusion of phagosomes with lysosomes and fusion of autophagosomes with lysosomes . There is also evidence that the mammalian HOPS protein VPS41 has additional functions that are independent of the complex in the fusion of lysosome‐associated membrane protein (LAMP) carriers with late endosomes , and the biogenesis of regulated secretory granules .…”

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confidence: 99%

Recruitment of VPS33A to HOPS by VPS16 Is Required for Lysosome Fusion with Endosomes and Autophagosomes

Wartosch

Günesdogan

Graham

et al. 2015

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The mammalian homotypic fusion and vacuole protein sorting (HOPS) complex is comprised of six subunits: VPS11, VPS16, VPS18, VPS39, VPS41 and the Sec1/Munc18 (SM) family member VPS33A. Human HOPS has been predicted to be a tethering complex required for fusion of intracellular compartments with lysosomes, but it remains unclear whether all HOPS subunits are required. We showed that the whole HOPS complex is required for fusion of endosomes with lysosomes by monitoring the delivery of endocytosed fluorescent dextran to lysosomes in cells depleted of individual HOPS proteins. We used the crystal structure of the VPS16/VPS33A complex to design VPS16 and VPS33A mutants that no longer bind each other and showed that, unlike the wild‐type proteins, these mutants no longer rescue lysosome fusion with endosomes or autophagosomes in cells depleted of the endogenous proteins. There was no effect of depleting either VIPAR or VPS33B, paralogs of VPS16 and VPS33A, on fusion of lysosomes with either endosomes or autophagosomes and immunoprecipitation showed that they form a complex distinct from HOPS. Our data demonstrate the necessity of recruiting the SM protein VPS33A to HOPS via its interaction with VPS16 and that HOPS proteins, but not VIPAR or VPS33B, are essential for fusion of endosomes or autophagosomes with lysosomes.

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“…The high embryonic lethality and impaired fertility of the ccz-1(ts) mutants confirmed the essential role of CCZ-1 in gametogenesis and embryogenesis (Nieto et al 2010). It has been reported that ccz-1 is involved in the digestion of apoptotic corpses, phagosome maturation, and processing of LROs in the intestine (Poteryaev et al 2007;Nieto et al 2010;Delahaye et al 2014). We found large droplets in the intestine, oocytes, and embryos of the ccz-1(ts) mutants (Figure 4, D-F, and Table S1).…”

Section: Mutant Embryos Of Ccz-1 Accumulate Enlarged Yolk-containing mentioning

confidence: 68%

“…These findings suggested that the loss of function of cpl-1 causes an enlargement of lipid-containing yolk complexes distinct from genuine lipid droplets. It has been shown that CCZ-1 acts in complex with SAND-1 as a guanine nucleotide exchange factor for RAB-7 and is involved in the digestion of apoptotic corpses, phagosome maturation, and the processing of lysosome-related organelles (Poteryaev et al 2007;Nieto et al 2010;Delahaye et al 2014). As found in the isolated ccz-1(ts) mutant embryos, sand-1 mutants also accumulate yolk-enriched large droplets in oocytes and embryos (Poteryaev and Spang 2005;Poteryaev et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Genetics of Lipid-Storage Management in Caenorhabditis elegans Embryos

et al. 2016

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Lipids play a pivotal role in embryogenesis as structural components of cellular membranes, as a source of energy, and as signaling molecules. On the basis of a collection of temperature-sensitive embryonic lethal mutants, a systematic database search, and a subsequent microscopic analysis of .300 interference RNA (RNAi)-treated/mutant worms, we identified a couple of evolutionary conserved genes associated with lipid storage in Caenorhabditis elegans embryos. The genes include cpl-1 (cathepsin L-like cysteine protease), ccz-1 (guanine nucleotide exchange factor subunit), and asm-3 (acid sphingomyelinase), which is closely related to the human Niemann-Pick disease-causing gene SMPD1. The respective mutant embryos accumulate enlarged droplets of neutral lipids (cpl-1) and yolk-containing lipid droplets (ccz-1) or have larger genuine lipid droplets (asm-3). The asm-3 mutant embryos additionally showed an enhanced resistance against C band ultraviolet (UV-C) light. Herein we propose that cpl-1, ccz-1, and asm-3 are genes required for the processing of lipid-containing droplets in C. elegans embryos. Owing to the high levels of conservation, the identified genes are also useful in studies of embryonic lipid storage in other organisms.

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Caenorhabditis elegansHOPS and CCZ-1 mediate trafficking to lysosome-related organelles independently of RAB-7 and SAND-1

Cited by 20 publications

References 149 publications

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes

Recruitment of VPS33A to HOPS by VPS16 Is Required for Lysosome Fusion with Endosomes and Autophagosomes

Genetics of Lipid-Storage Management in Caenorhabditis elegans Embryos

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