LRRK 2 to the rescue of damaged endomembranes
2020; Springer Nature; Volume: 39; Issue: 18 Linguagem: Inglês
10.15252/embj.2020106162
ISSN1460-2075
AutoresMaja Radulovic, Harald Stenmark,
Tópico(s)Calcium signaling and nucleotide metabolism
ResumoNews & Views16 August 2020free access LRRK2 to the rescue of damaged endomembranes Maja Radulovic Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway Search for more papers by this author Harald Stenmark Corresponding Author [email protected] orcid.org/0000-0002-1971-4252 Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway Centre of Molecular Inflammation Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway Search for more papers by this author Maja Radulovic Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway Search for more papers by this author Harald Stenmark Corresponding Author [email protected] orcid.org/0000-0002-1971-4252 Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway Centre of Molecular Inflammation Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway Search for more papers by this author Author Information Maja Radulovic1,2 and Harald Stenmark *,1,2,3 1Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway 2Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 3Centre of Molecular Inflammation Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway *Corresponding author. Tel: +47 22781818; Fax: +47 22781845; E-mail: [email protected] EMBO J (2020)39:e106162https://doi.org/10.15252/embj.2020106162 See also: S Herbst et al (September 2020) PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Mutations in several genes encoding for lysosomal proteins are involved in Parkinson's disease (PD). In this issue, Herbst et al (2020) show that PD-related leucine-rich repeat kinase 2 (LRRK2) is activated in response to pathogen or membranolytic drug-induced damage of phagolysosomes and lysosomes in macrophages, and regulates endolysosomal homeostasis by controlling the balance between membrane repair and degradation. Originally regarded merely as degradative organelles, lysosomes have emerged as dynamic signaling platforms. Equipped with an array of over 50 hydrolytic enzymes, high concentrations of Ca2+ and other bivalent cations, and a luminal pH lower than 5, lysosomes are indispensable for cellular degradation and play a pivotal role in coordinating cellular metabolism, intracellular signaling, organelle contact, and fusion (Ballabio & Bonifacino, 2020). Given the nature of their contents and the multiple functions they play, it comes as no surprise that even minor interference with lysosomal membrane integrity may have devastating consequences for cell survival. Indeed, dysfunctional lysosomes result in metabolic disorders, inflammation, and neurodegenerative diseases. To circumvent the harmful consequences that may arise from compromised lysosomal membrane integrity, cells have dedicated a pathway for clearance of damaged lysosomes, namely an autophagic process known as lysophagy. However, safeguard mechanisms to deal with minor lesions in lysosomal membranes have been unknown. Recently, it has been discovered that limited endolysosomal membrane damage relies on rapid recruitment of the endosomal sorting complex required for transport (ESCRT) machinery (Radulovic et al, 2018; Skowyra et al, 2018). Upon lysosomal membrane permeabilization, the ESCRT-I protein TSG101 together with the ESCRT-III-associated protein ALIX recruits the ESCRT-III protein CHMP4B, a mediator of lysosomal membrane repair, to seal damaged membranes. These findings raised the question of what recruits the ESCRT machinery to the site of the damage. In their paper, Herbst and colleagues elegantly address this and reveal that, in macrophages, LRRK2 recruits the small GTPase Rab8A and CHMP4B to damaged endolysosomes, thereby controlling the decision between membrane repair and lysophagy (Fig 1) (Herbst et al, 2020). LRRK2 is a multidomain protein kinase that phosphorylates various members of the Rab GTPase family. It is expressed in a broad range of organs and tissues, and its deregulation has been noted not only in PD but also in Crohn's disease (Hui et al, 2018; Kuwahara & Iwatsubo, 2020). Figure 1. LRRK2 activation controls the repair of damaged endomembranes in macrophagesIn macrophages, LRRK2 activation is triggered by pathogen or chemically induced damage of phagolysosome or lysosome. Once activated, LRRK2 phosphorylates the small GTPase Rab8A which, in response to Ca2+ flux out of the lysosome, recruits the ESCRT-III protein CHMP4B to mediate endolysosomal membrane repair. In the absence of LRRK2 and Rab8A, the recruitment of ESCRT-III is impaired and lysophagy is initiated by galectin-3, which recruits LC3B-containing autophagic membranes to initiate clearance of the damaged lysosome by lysophagy. Download figure Download PowerPoint Although LRRK2 translocation to enlarged lysosomes upon lysosomal stress inducers has been reported, it has remained unclear whether endolysosomal damage is implicated in LRRK2 activation (Eguchi et al, 2018). Indeed, Herbst and colleagues observed that LRRK2 is activated in response to pathogen-induced phagosomal membrane damage or the lysosomotropic drug L-leucyl-L-leucine methyl ester (LLOMe). Once activated, LRRK2 triggers a series of events, including phosphorylation of Rab8A which, in response to Ca2+ signaling, coordinates the recruitment of ESCRT-III. The absence of LRRK2 and Rab8A or inhibition of LRRK2 kinase activity impairs the recruitment of ESCRT-III upon LLOMe-induced damage. In addition, a number of vesicles positive for the lysosomal integrity marker galectin-3 (Gal3), a cytosolic lectin that recognizes luminally exposed sugars, is significantly reduced. This indicates that lysosomal damage that occurs in the absence of LRRK2 signaling cannot be repaired, and thus, lysophagy is initiated by galectins to clear the damaged organelles. In line with these findings, in the absence of LRRK2/Rab8A function, an increased localization of the autophagy protein LC3B to damaged lysosomes is observed. Recently, it has been demonstrated that Gal3 coordinates both ESCRT recruitment and the autophagic response to damaged endolysosomes (Jia et al, 2020), in part by interacting with the ESCRT-III-associated protein ALIX. Interestingly, both Gal3 and ALIX, which are initially recruited by Ca2+ flux out of the lysosome, are required for the restoration of lysosomal function after lysosomal damage. In this context, it would be interesting to explore possible connections between LRRK2 and Gal3, and further investigate the function of ALIX under LRRK2 knockout conditions. These recent findings highlight the complex nature of the lysosomal membrane repair process and show how cells rely on multiple components to orchestrate the repair of damaged membranes. The question of how the repair process is coordinated by these multiple components requires further attention. Is intracellular Ca2+ flux the only signal that triggers LRRK2 recruitment to damaged endomembranes? Are there multiple sensors of endolysosomal damage? How is Rab8A, a GTPase, classically associated with exocytosis, recruited, and are other LRRK2-responsive Rab GTPases involved? Furthermore, depending on the nature of the damage, multiple mechanisms to repair damaged lysosomes may exist. Recently, a role for LRRK2 in mediating tubulation and membrane sorting from damaged lysosomes was described (preprint: Bonet-Ponce et al, 2020). It will be interesting to explore whether and how the ESCRT machinery contributes to this process as they assemble at the cytosolic face of the neck of the forming involution (Vietri et al, 2020). Given the central role of lysosomes in maintaining proper cellular homeostasis, mechanisms that ensure lysosomal structural integrity are of great importance. The discovery by Herbst and colleagues provides novel insight into the cellular mechanism by discovering the roles of LRRK2 and Rab8A in ESCRT-III recruitment. Importantly, the authors also find that monocyte-derived macrophages from PD patients with LRRK2 gain-of-function mutations accumulate vesicles that are positive for Rab8A and Gal3, suggesting a new link between endolysosomal damage and PD. Surprisingly, under steady-state conditions macrophages from PD patients, besides elevated levels of Rab8A phosphorylation, had increased number of Gal3-positive vesicles, showing that LRRK2 gain of function may drive Gal3 recruitment to endolysosomes. This suggests that the balance between lysosomal repair and clearance might be altered in PD patients. This is an important study that offers a novel mechanistic explanation of the role of LRRK2 in PD in addition to the previously identified function for LRRK2 in the formation of primary cilia in PD-associated regions of the brain (Dhekne et al, 2018). Future research should seek to understand more about the changes associated with LRRK2 mutations in PD and translate this knowledge into therapies for patients with genetic mutations (Whiffin et al, 2020). References Ballabio A, Bonifacino JS (2020) Lysosomes as dynamic regulators of cell and organismal homeostasis. 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Nat Rev Mol Cell Biol 21: 25–42CrossrefCASPubMedWeb of Science®Google Scholar Whiffin N, Armean IM, Kleinman A, Marshall JL, Minikel EV, Goodrich JK, Quaife NM, Cole JB, Wang Q, Karczewski KJ et al (2020) The effect of LRRK2 loss-of-function variants in humans. Nat Med 26: 869–877CrossrefCASPubMedWeb of Science®Google Scholar Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 39,Issue 18,15 September 2020This month's cover highlights the article Highly active rubiscos discovered by systematic interrogation of natural sequence diversity by Dan Davidi, Melina Shamshoum, Zhijun Guo, Ron Milo and colleagues. For decades scientists have tried to improve the carbon fixation enzyme rubisco. Here, the authors asked if evolution already gave rise to fast variants. An extensive survey of the natural sequence space resulted in the discovery of the fastest rubisco found to date. (Cover illustration by Sandra Krahl) Volume 39Issue 1815 September 2020In this issue FiguresReferencesRelatedDetailsLoading ...
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