NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

Davis, Oliver B.; Shin, H; Lim, Chaesung; Wu, Emma; Kukurugya, Matthew A.; Maher, Claire; Perera, Rushika M.; Ordoñez, M. Paulina; Zoncu, Roberto

doi:10.1016/j.devcel.2020.11.016

Cited by 139 publications

(118 citation statements)

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“…In support for a causal role between LRH-1 and STARD1, previous reports in human granulosa tumor cells indicated that LRH-1 transactivates the STARD1 promoter through the −105 to −95 site, while targeted loss of LRH-1 in granulosa cells decreased STARD1 mRNA levels and progesterone production in transgenic mice in response to human chorionic gonadotrophin, causing a failure to ovulate [ 43 , 44 ]. Similar to the ability of ACDase to preserve mitochondrial performance despite lysosomal cholesterol storage, recent findings linked lysosomal and mitochondrial dysfunction in NPC disease to mTORC1 hyperactivation [ 45 ]. Interestingly, genetic and pharmacological inhibition of mTORC1 improved mitochondrial function without correcting lysosomal cholesterol accumulation [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation

et al. 2021

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Niemann-Pick type C (NPC) disease, a lysosomal storage disorder caused by defective NPC1/NPC2 function, results in the accumulation of cholesterol and glycosphingolipids in lysosomes of affected organs, such as liver and brain. Moreover, increase of mitochondrial cholesterol (mchol) content and impaired mitochondrial function and GSH depletion contribute to NPC disease. However, the underlying mechanism of mchol accumulation in NPC disease remains unknown. As STARD1 is crucial in intramitochondrial cholesterol trafficking and acid ceramidase (ACDase) has been shown to regulate STARD1, we explored the functional relationship between ACDase and STARD1 in NPC disease. Liver and brain of Npc1 −/− mice presented a significant increase in mchol levels and STARD1 expression. U18666A, an amphiphilic sterol that inhibits lysosomal cholesterol efflux, increased mchol levels in hepatocytes from Stard1 f/f mice but not Stard1 ΔHep mice. We dissociate the induction of STARD1 expression from endoplasmic reticulum stress, and establish an inverse relationship between ACDase and STARD1 expression and LRH-1 levels. Hepatocytes from Npc1 +/+ mice treated with U18666A exhibited increased mchol accumulation, STARD1 upregulation and decreased ACDase expression, effects that were reversed by cholesterol extraction with 2-hydroxypropyl-β-cyclodextrin. Moreover, transfection of fibroblasts from NPC patients with ACDase, decreased STARD1 expression and mchol accumulation, resulting in increased mitochondrial GSH levels, improved mitochondrial functional performance, decreased oxidative stress and protected NPC fibroblasts against oxidative stress-mediated cell death. Our results demonstrate a cholesterol-dependent inverse relationship between ACDase and STARD1 and provide a novel approach to target the accumulation of cholesterol in mitochondria in NPC disease.

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Section: Discussionmentioning

confidence: 99%

Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation

et al. 2021

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“…While multiple cargo receptors are recruited to damaged lysosomes (Figure 4C-E) (Davis et al, 2021;Koerver et al, 2019;Papadopoulos et al, 2017), to date, the cargo receptors critical for linking damaged lysosomes to the core autophagy machinery have not been clearly delineated, although knockdown of SQSTM1 has been reported to result in reduced lysophagic flux (Papadopoulos et al, 2017). We therefore systematically probe cargo receptor involvement in lysophagy.…”

Section: Measurement Of Lysophagic Flux With Lyso-keimamentioning

confidence: 99%

“…In addition, multiple Ub-binding cargo receptors including OPTN, CALCOCO2 and TAX1BP1 are recruited to ubiquitylated bacteria and are required for efficient xenophagy in various contexts (Thurston, 2009a;Thurston et al, 2012;Tumbarello et al, 2015;Wild et al, 2011). While multiple cargo receptors including have been reported to be recruited to damaged lysosomes (Bussi et al, 2018;Davis et al, 2021;Koerver et al, 2019), the underlying mechanisms for recruitment, the identity of the receptors critical for lysophagic flux, and the reasons for the diversity of receptors that are recruited remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy

Eapen

Swarup

Hoyer

et al. 2021

Preprint

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Removal of damaged organelles via the process of selective autophagy constitutes a major form of cellular quality control. Damaged organelles are recognized by a dedicated surveillance machinery, leading to the assembly of an autophagosome around the damaged organelle, prior to fusion with the degradative lysosomal compartment. Lysosomes themselves are also prone to damage and are degraded through the process of lysophagy. While early steps involve recognition of ruptured lysosomal membranes by glycan-binding Galectins and ubiquitylation of transmembrane lysosomal proteins, many steps in the process, and their inter-relationships, remain poorly understood, including the role and identity of cargo receptors required for completion of lysophagy. Here, we employ quantitative organelle capture and proximity biotinylation proteomics of autophagy adaptors, cargo receptors, and Galectins in response to acute lysosomal damage, thereby revealing the landscape of lysosomal proteome remodeling during lysophagy. Among proteins dynamically recruited to damaged lysosomes were ubiquitin-binding autophagic cargo receptors. Using newly developed lysophagic flux reporters including Lyso-Keima, we demonstrate that TAX1BP1, together with its associated kinase TBK1, are both necessary and sufficient to promote lysophagic flux in both Hela cells and induced neurons (iNeurons). While the related receptor OPTN can drive damage-dependent lysophagy when overexpressed, cells lacking either OPTN or CALCOCO2 still maintain significant lysophagic flux in HeLa cells. Mechanistically, TAX1BP1-driven lysophagy requires its N-terminal SKICH domain, which binds both TBK1 and the autophagy regulatory factor RB1CC1, and requires upstream ubiquitylation events for efficient recruitment and lysophagic flux. These results identify TAX1BP1 as a central component in the lysophagy pathway and provide a proteomic resource for future studies of the lysophagy process.

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“…OSBP1-mediated cholesterol transfer from the ER to endolysosomes is increased in NPC1-null cells, resulting in aberrant mTORC1 activation (Lim et al 2019). Pharmacological suppression of mTORC1 signaling can correct several aspects of cellular function independent of the cholesterol storage defect, thus implicating dysregulated mTORC1 signaling as a likely driver of pathology in Niemann-Pick type C (Davis et al 2021). Similarly, another lipid transfer protein ORP1L mediates bidirectional cholesterol transfer between the ER and endolysosomes through interaction with three different ER receptors: VAPA, VAPB, or MOSPD2 (Rocha et al 2009;Zhao and Ridgway 2017;Di Mattia et al 2018;Zhao et al 2020).…”

Section: Contact Sites Involved In Lipid Metabolismmentioning

confidence: 99%

Interorganelle communication, aging, and neurodegeneration

Petković

Jan

2021

Genes Dev.

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Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics.

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NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

Abstract: Highlights d Proteomic profiling of NPC lysosomes reveals both proteolytic and structural defects d Loss of cholesterol transport activity by NPC1 causes aberrant mTORC1 signaling d mTORC1 inhibition restores lysosomal and mitochondrial function in NPC cells

Cited by 139 publications

References 104 publications

Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation

Acid ceramidase improves mitochondrial function and oxidative stress in Niemann-Pick type C disease by repressing STARD1 expression and mitochondrial cholesterol accumulation

Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy

Interorganelle communication, aging, and neurodegeneration

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