Lysosome biology in autophagy

Yim, Willa Wen-You; Mizushima, Noboru

doi:10.1038/s41421-020-0141-7

Cited by 533 publications

(367 citation statements)

References 151 publications

(229 reference statements)

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“…This finding may suggest that GM2 ganglioside accumulation could promote the disruption of the lysosome and the release of the ganglioside, as has been described for some mucopolysaccharidoses (MPS) [ 63 ]. Since the lysosome has a pivotal function in the degradation of several macromolecules and organelles [ 64 , 65 , 66 ], its impairment will affect the cellular homeostasis with a negative impact on the global tissue physiology. Here we described the current findings of the physiopathology of these disorders, which are summarized in Figure 4 .…”

Section: Physiopathology Of Gm2 Gangliosidosesmentioning

confidence: 99%

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Leal

Benincore-Flórez

Solano-Galarza

et al. 2020

IJMS

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GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

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Section: Physiopathology Of Gm2 Gangliosidosesmentioning

confidence: 99%

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Leal

Benincore-Flórez

Solano-Galarza

et al. 2020

IJMS

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“…The next topological transformation is fusion of the outer autophagosomal membrane with an endosome or lysosome to generate a hybrid lytic organelle. This step depends on SNARE proteins, the main mediators of membrane fusion (Yim and Mizushima, 2020). As a result, a onemembrane vesicle called a macroautophagic body is released into the lytic organelle and degraded.…”

Section: Introductionmentioning

confidence: 99%

Microautophagy – distinct molecular mechanisms handle cargoes of many sizes

Schuck

2020

Journal of Cell Science

248

180

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Autophagy is fundamental for cell and organismal health. Two types of autophagy are conserved in eukaryotes: macroautophagy and microautophagy. During macroautophagy, autophagosomes deliver cytoplasmic constituents to endosomes or lysosomes, whereas during microautophagy lytic organelles take up cytoplasm directly. While macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become clear that microautophagy has a broad range of functions in biosynthetic transport, metabolic adaptation, organelle remodeling and quality control. This Review discusses the selective and non-selective microautophagic processes known in yeast, plants and animals. Based on the molecular mechanisms for the uptake of microautophagic cargo into lytic organelles, I propose to distinguish between fission-type microautophagy, which depends on ESCRT proteins, and fusion-type microautophagy, which requires the core autophagy machinery and SNARE proteins. Many questions remain to be explored, but the functional versatility and mechanistic diversity of microautophagy are beginning to emerge.

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“…Lysosomes are dynamic organelles, whose intracellular position and movement are critical for their signaling functions, maturation, turnover and interaction with other membrane organelles (Bonifacino and Neefjes, 2017;Luzio et al, 2007;Saftig and Klumperman, 2009;Savini et al, 2019). In response to nutritional and oxidative stress, lysosomes mobilize to perinuclear areas of the cytoplasm, where they fuse with autophagosomes (Lim and Zoncu, 2016;Yim and Mizushima, 2020). Similarly, lysosomes traffic retrogradely to bacteria undergoing autophagy (Hu et al, 2020) and anterogradely to plasma membrane sites of repair (Andrews and Corrotte, 2018), and exocytose in migrating and immune cells (Castro-Castro et al, 2016;Lettau et al, 2007;Wilson et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

A septin GTPase scaffold of dynein-dynactin motors triggers retrograde lysosome transport

Kesisova

Robinson

Spiliotis

2020

Preprint

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The intracellular position of lysosomes is critical for cell metabolism and signaling. Kesisova et al discovered a membrane-associated septin GTPase scaffold of dynein-dynactin that promotes retrograde traffic and perinuclear lysosome clustering at steady state and in response to oxidative stress. Condensed title: A septin GTPase mechanism of dynein-driven traffic Abbreviations: amino acids, aa; dynein heavy chain, DHC; dynein intermediate chain, DIC, dynein light intermediate chain, DLIC; early endosome antigen 1, EEA1; early sorting complex required for transport, ESCRT; G-domain, GTPase domain; guanosine-5′-triphosphate, GTP; guanosine diphosphate, GDP; guanosine 5′-O-[γ-thio]triphosphate, GTPγS; JNK-interaction protein-1, JIP-1; lysosomal associated membrane protein 1, LAMP1; late endosomal/lysosomal adaptor, MAPK and mTOR activator 4, LAMTOR4; multivesicular body, MVB; N-terminal extension, NTE; reactive oxygen species, ROS; septin, SEPT; tumor susceptibility gene 101, TSG101. AbstractThe metabolic and signaling functions of lysosomes depend on their intracellular positioning and trafficking, but the underlying mechanisms are little understood. Here, we have discovered a novel septin GTPase-based mechanism for retrograde lysosome transport. We found that septin 9 (SEPT9) associates with lysosomes, promoting the perinuclear localization of lysosomes in a Rab7-independent manner. SEPT9 targeting to mitochondria and peroxisomes is sufficient to recruit dynein and cause perinuclear clustering. We show that SEPT9 interacts with both dynein and dynactin through its GTPase domain and N-terminal extension, respectively. Strikingly, SEPT9 associates preferentially with the dynein intermediate chain (DIC) in its GDP-bound state, which favors dimerization and assembly into septin multimers. In response to oxidative cell stress induced by arsenite, SEPT9 localization to lysosomes is enhanced, promoting the perinuclear clustering of lysosomes. We posit that septins function as GDP-activated scaffolds for the cooperative assembly of dynein-dynactin, providing an alternative mechanism of retrograde lysosome transport at steady state and during cellular adaptation to stress. barriers, which control protein localization in a spatiotemporal specific manner (Bridges and Gladfelter, 2015;Caudron and Barral, 2009). In the endocytic pathway, septins associate preferentially with endolysosomes that are enriched with phosphatidylinositol 3,5-bisphosphate and Rab7 (Dolat and Spiliotis, 2016). Moreover, septins are critical for lysosome merging with macropinosomes and Shigella bacteria undergoing autophagy (Dolat and Spiliotis, 2016;Krokowski et al., 2018). In a proteomic study of the dynein interactome, septins were identified as potential binding partners of DIC, DLIC and the dynein adaptor BiCD2 (Redwine et al., 2017).Here, we report that membrane-associated septins provide a novel GDP-activated mechanism for the retrograde dynein-driven transport of lysosomes.

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Lysosome biology in autophagy

Cited by 533 publications

References 151 publications

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

Microautophagy – distinct molecular mechanisms handle cargoes of many sizes

A septin GTPase scaffold of dynein-dynactin motors triggers retrograde lysosome transport

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