DENND6A Links Arl8b to a Rab34/RILP/dynein Complex, Regulating Lysosomal Positioning and Autophagy

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jan 31

PMID 38296963

Authors

Rahul Kumar

Maleeha Khan

Vincent Francis

Adriana Aguila

Gopinath Kulasekaran

Emily Banks

Peter S McPherson

Affiliations

Soon will be listed here.

Abstract

Lysosomes help maintain cellular proteostasis, and defects in lysosomal positioning and function can cause disease, including neurodegenerative disorders. The spatiotemporal distribution of lysosomes is regulated by small GTPases including Rabs, which are activated by guanine nucleotide exchange factors (GEFs). DENN domain proteins are the largest family of Rab GEFs. Using a cell-based assay, we screened DENND6A, a member of the DENN domain protein family against all known Rabs and identified it as a potential GEF for 20 Rabs, including Rab34. Here, we demonstrate that DENND6A activates Rab34, which recruits a RILP/dynein complex to lysosomes, promoting lysosome retrograde transport. Further, we identify DENND6A as an effector of Arl8b, a major regulatory GTPase on lysosomes. We demonstrate that Arl8b recruits DENND6A to peripheral lysosomes to activate Rab34 and initiate retrograde transport, regulating nutrient-dependent lysosomal juxtanuclear repositioning. Loss of DENND6A impairs autophagic flux. Our findings support a model whereby Arl8b/DENND6A/Rab34-dependent lysosomal retrograde trafficking controls autophagy.

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References

Blumer J, Rey J, Dehmelt L, Mazel T, Wu Y, Bastiaens P . RabGEFs are a major determinant for specific Rab membrane targeting. J Cell Biol. 2013; 200(3):287-300. PMC: 3563681. DOI: 10.1083/jcb.201209113. View

Li M, Jaffe A, Straub R, Tao R, Shin J, Wang Y . A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus. Nat Med. 2016; 22(6):649-56. DOI: 10.1038/nm.4096. View

Starling G, Yip Y, Sanger A, Morton P, Eden E, Dodding M . Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes. EMBO Rep. 2016; 17(6):823-41. PMC: 4893818. DOI: 10.15252/embr.201541382. View

Ballabio A, Bonifacino J . Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2019; 21(2):101-118. DOI: 10.1038/s41580-019-0185-4. View

Ghosh S, Dellibovi-Ragheb T, Kerviel A, Pak E, Qiu Q, Fisher M . β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway. Cell. 2020; 183(6):1520-1535.e14. PMC: 7590812. DOI: 10.1016/j.cell.2020.10.039. View

Kumar R, Francis V, Kulasekaran G, Khan M, Armstrong G, McPherson P . A cell-based GEF assay reveals new substrates for DENN domains and a role for DENND2B in primary ciliogenesis. Sci Adv. 2022; 8(8):eabk3088. PMC: 8865772. DOI: 10.1126/sciadv.abk3088. View

Sindhwani A, Arya S, Kaur H, Jagga D, Tuli A, Sharma M . Salmonella exploits the host endolysosomal tethering factor HOPS complex to promote its intravacuolar replication. PLoS Pathog. 2017; 13(10):e1006700. PMC: 5679646. DOI: 10.1371/journal.ppat.1006700. View

Pankiv S, Alemu E, Brech A, Bruun J, Lamark T, Overvatn A . FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J Cell Biol. 2010; 188(2):253-69. PMC: 2812517. DOI: 10.1083/jcb.200907015. View

Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, Boscheron C . Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet. 2013; 45(6):639-47. PMC: 3826256. DOI: 10.1038/ng.2613. View

10.

Spits M, Heesterbeek I, Voortman L, Akkermans J, Wijdeven R, Cabukusta B . Mobile late endosomes modulate peripheral endoplasmic reticulum network architecture. EMBO Rep. 2021; 22(3):e50815. PMC: 7926257. DOI: 10.15252/embr.202050815. View

11.

Rosa-Ferreira C, Munro S . Arl8 and SKIP act together to link lysosomes to kinesin-1. Dev Cell. 2011; 21(6):1171-8. PMC: 3240744. DOI: 10.1016/j.devcel.2011.10.007. View

12.

Li X, Rydzewski N, Hider A, Zhang X, Yang J, Wang W . A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol. 2016; 18(4):404-17. PMC: 4871318. DOI: 10.1038/ncb3324. View

13.

Vidal M . Exosomes: Revisiting their role as "garbage bags". Traffic. 2019; 20(11):815-828. DOI: 10.1111/tra.12687. View

14.

Shang L, Chen S, Du F, Li S, Zhao L, Wang X . Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A. 2011; 108(12):4788-93. PMC: 3064373. DOI: 10.1073/pnas.1100844108. View

15.

Yang Z, Klionsky D . Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2009; 22(2):124-31. PMC: 2854249. DOI: 10.1016/j.ceb.2009.11.014. View

16.

Keren-Kaplan T, Bonifacino J . ARL8 Relieves SKIP Autoinhibition to Enable Coupling of Lysosomes to Kinesin-1. Curr Biol. 2020; 31(3):540-554.e5. PMC: 7878431. DOI: 10.1016/j.cub.2020.10.071. View

17.

Goldenberg N, Grinstein S, Silverman M . Golgi-bound Rab34 is a novel member of the secretory pathway. Mol Biol Cell. 2007; 18(12):4762-71. PMC: 2096593. DOI: 10.1091/mbc.e06-11-0991. View

18.

Lu M, van Tartwijk F, Lin J, Nijenhuis W, Parutto P, Fantham M . The structure and global distribution of the endoplasmic reticulum network are actively regulated by lysosomes. Sci Adv. 2020; 6(51). PMC: 7744115. DOI: 10.1126/sciadv.abc7209. View

19.

Saric A, Freeman S, Williamson C, Jarnik M, Guardia C, Fernandopulle M . SNX19 restricts endolysosome motility through contacts with the endoplasmic reticulum. Nat Commun. 2021; 12(1):4552. PMC: 8316374. DOI: 10.1038/s41467-021-24709-1. View

20.

Rocha N, Kuijl C, van der Kant R, Janssen L, Houben D, Janssen H . Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning. J Cell Biol. 2009; 185(7):1209-25. PMC: 2712958. DOI: 10.1083/jcb.200811005. View