The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes

Marwaha, Rituraj; Arya, Subhash B.; Jagga, Divya; Kaur, Harmeet; Tuli, Amit; Sharma, Mahak

doi:10.1083/jcb.201607085

Cited by 134 publications

(153 citation statements)

References 37 publications

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“…To study transport route selectivity operational on endolysosomes, we examined the interplay between their associated GTPases, Rab7, and Arl8b. In agreement with previous findings (Marwaha et al , ), we noted that part of the repertoire populated by Rab7 also carries Arl8b (Fig A and B). It has been speculated that Arl8b marks a later maturation stage as compared to Rab7 (Hofmann & Munro, ; Garg et al , ), and we therefore considered whether Rab7 activity status affects localization and behaviour of Arl8b.…”

Section: Resultssupporting

confidence: 94%

SKIP ‐ HOPS recruits TBC 1D15 for a Rab7‐to‐Arl8b identity switch to control late endosome transport

et al. 2020

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The endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or “late” endosomes are designated by small membrane‐bound GTPases Rab7 and Arl8b, which can either operate independently or collaborate to form a joint compartment. Whether, and how, Rab7 and Arl8b resolve this hybrid identity compartment to regain functional autonomy is unknown. Here, we report that Arl8b employs its effector SKIP to instigate inactivation and removal of Rab7 from select membranes. We find that SKIP interacts with Rab7 and functions as its negative effector, delivering the cognate GAP, TBC1D15. Recruitment of TBC1D15 to SKIP occurs via the HOPS complex, whose assembly is facilitated by contacts between Rab7 and the KMI motif of SKIP. Consequently, SKIP mediates reinstatement of single identity Arl8b sub‐compartment through an ordered Rab7‐to‐Arl8b handover, and, together with Rab7's positive effector RILP, enforces spatial, temporal and morphological compartmentalization of endolysosomal organelles.

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Section: Resultssupporting

confidence: 94%

SKIP ‐ HOPS recruits TBC 1D15 for a Rab7‐to‐Arl8b identity switch to control late endosome transport

et al. 2020

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“…In addition, Rab7 is still required for LE-lysosome fusion in Drosophila [79,86]. This suggests that Rab7 may assist in the tethering process, perhaps by recruiting the conserved LE/lysosomal adaptor PLEKHM1 (FlyBase Annotation Symbol CG6613) which is strongly precipitated by activated Drosophila Rab7 [48] and in mammals facilitates LE-lysosome fusion [87,88]. …”

Section: Discussionmentioning

confidence: 99%

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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“…To confirm the effect of Arl8b on lysosome motility, we decreased the cytoplasmic pH of control- and Arl8b- siRNA treated HeLa cells from pH 7.2 to 6.5. Previous studies have demonstrated that lysosomes traffic toward the plasma membrane in response to acidic pH (34, 41, 43). At pH 7.2 control siRNA transfected cells showed a normal perinuclear distribution.…”

Section: Resultsmentioning

confidence: 99%

“…Based on which effector Arl8b binds (HOPS complex, PLEKHM1 or SKIP/Kif5b), it can control the delivery of endocytosed material to lysosomes (29, 31–32, 34–35) or control lysosome and lysosome-related organelle motility toward the cell periphery, respectively (36–37). Rosa-Ferreira et al identified SKIP and kinesin-1 as Arl8b binding-partners in directing conventional lysosomes to the cell periphery (37).…”

Section: Discussionmentioning

confidence: 99%

“…We and others showed that Arl8b controls delivery of cargoes to the lysosome by binding to its effectors HOPS complex and PLEKHM1, permitting fusion of endosomes and autophagosomes to lysosomes (29–34). Thus, Arl8b has been shown to play a central role in regulating lipid- and peptide-antigen presentation through CD1d and MHC class II, respectively (31, 35).…”

Section: Introductionmentioning

confidence: 99%

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Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Mycobacterium tuberculosis Infection

Michelet

Tuli

Gan

et al. 2018

The Journal of Immunology

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Mycobacterium tuberculosis (Mtb) is an extremely successful pathogen and its success is widely attributed to its ability to manipulate the intracellular environment of macrophages. A central phenomenon of tuberculosis pathology enabling immune evasion is the capacity of virulent Mtb (H37Rv) to induce macrophage necrosis, which facilitates the escape of the mycobacteria from the macrophage and spread of infection. In contrast, avirulent Mtb (H37Ra) induces macrophage apoptosis, which permits antigen presentation and activation of adaptive immunity. Previously, we found that H37Rv induces plasma membrane microdisruptions, leading to necrosis in the absence of plasma membrane repair. In contrast, H37Ra permits plasma membrane repair which changes the host cell death modality to apoptosis suggesting that membrane repair is critical for sequestering the pathogen in apoptotic vesicles. However, mechanisms of plasma membrane repair induced in response to Mtb infection remain unknown. Plasma membrane repair is known to induce a Ca2+-mediated signaling, which recruits lysosomes to the area of damaged plasma membrane sites for its resealing. Here, we found that the small GTPase-Arl8b is required for plasma membrane repair by controlling the exocytosis of lysosomes in cell lines and in human primary macrophages. Importantly, we found that the Arl8b secretion pathway is crucial to control the type of cell death of the Mtb infected macrophages. Indeed, Arl8b depleted macrophages infected with avirulent H37Ra undergo necrotic instead of apoptotic cell death. These findings suggest that membrane repair mediated by Arl8b may be an important mechanism distinguishing avirulent from virulent Mtb induced necrotic cell death.

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The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes

Cited by 134 publications

References 37 publications

SKIP ‐ HOPS recruits TBC 1D15 for a Rab7‐to‐Arl8b identity switch to control late endosome transport

SKIP ‐ HOPS recruits TBC 1D15 for a Rab7‐to‐Arl8b identity switch to control late endosome transport

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

Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Mycobacterium tuberculosis Infection

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