Lysosomal size matters

Araújo, Mariana E. G. de; Liebscher, Gudrun; Hess, Michael W.; Huber, Lukas A.

doi:10.1111/tra.12714

Cited by 150 publications

(134 citation statements)

References 205 publications

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“…In some models, lipid accumulation in LE/Lys inhibits lysosomal cathepsins, leading to impaired degradation of lysosomal cargo and increased autophagic intermediates [14]. However, in the latter experiments described above (Supplementary Figure S1), DQ-Red-BSA degradation was increased in CHO M12 cells, and we hypothesize that possibly the enlarged LE/Lys compartment in these NPC1 mutant cells [45,46] may be one of the underlying causes for this observation. We have previously reported a reduction in the size of the LE/Lys compartment in AnxA6-depleted NPC1 mutant cells Therefore, we examined the bulk degradation using fluorescently-labeled DQ-Red-BSA as cargo [41], which is internalized and transported to lysosomes and then cleaved, resulting in a bright red fluorescent signal.…”

Section: Anxa6 Expression In Npc1 Mutant Cellsmentioning

confidence: 75%

Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells

Meneses‐Salas

García-Melero

Blanco‐Muñoz

et al. 2020

Cells

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We recently identified elevated annexin A6 (AnxA6) protein levels in Niemann–Pick-type C1 (NPC1) mutant cells. In these cells, AnxA6 depletion rescued the cholesterol accumulation associated with NPC1 deficiency. Here, we demonstrate that elevated AnxA6 protein levels in NPC1 mutants or upon pharmacological NPC1 inhibition, using U18666A, were not due to upregulated AnxA6 mRNA expression, but caused by defects in AnxA6 protein degradation. Two KFERQ-motifs are believed to target AnxA6 to lysosomes for chaperone-mediated autophagy (CMA), and we hypothesized that the cholesterol accumulation in endolysosomes (LE/Lys) triggered by the NPC1 inhibition could interfere with the CMA pathway. Therefore, AnxA6 protein amounts and cholesterol levels in the LE/Lys (LE-Chol) compartment were analyzed in NPC1 mutant cells ectopically expressing lysosome-associated membrane protein 2A (Lamp2A), which is well known to induce the CMA pathway. Strikingly, AnxA6 protein amounts were strongly decreased and coincided with significantly reduced LE-Chol levels in NPC1 mutant cells upon Lamp2A overexpression. Therefore, these findings suggest Lamp2A-mediated restoration of CMA in NPC1 mutant cells to lower LE-Chol levels with concomitant lysosomal AnxA6 degradation. Collectively, we propose CMA to permit a feedback loop between AnxA6 and cholesterol levels in LE/Lys, encompassing a novel mechanism for regulating cholesterol homeostasis in NPC1 disease.

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Section: Anxa6 Expression In Npc1 Mutant Cellsmentioning

confidence: 75%

Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells

Meneses‐Salas

García-Melero

Blanco‐Muñoz

et al. 2020

Cells

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“…2d . The size of the lysosomes may be related to lysosomal activity, but the contribution remains somewhat obscure 55 . Several proteins have been found to affect lysosomal size.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation

Onodera

Giaccia

et al. 2020

Commun Biol

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Enhanced invasiveness, a critical determinant of metastasis and poor prognosis, has been observed in cancer cells that survive cancer therapy, including radiotherapy. Here, we show that invasiveness in radiation-surviving cancer cells is associated with alterations in lysosomal exocytosis caused by the enhanced activation of Arl8b, a small GTPase that regulates lysosomal trafficking. The binding of Arl8b with its effector, SKIP, is increased after radiation through regulation of BORC-subunits. Knockdown of Arl8b or BORC-subunits decreases lysosomal exocytosis and the invasiveness of radiation-surviving cells. Notably, high expression of ARL8B and BORC-subunit genes is significantly correlated with poor prognosis in breast cancer patients. Sp1, an ATM-regulated transcription factor, is found to increase BORC-subunit genes expression after radiation. In vivo experiments show that ablation of Arl8b decreases IR-induced invasive tumor growth and distant metastasis. These findings suggest that BORC-Arl8b-mediated lysosomal trafficking is a target for improving radiotherapy by inhibiting invasive tumor growth and metastasis.

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“…Beyond the lysosome's canonical role in cellular waste disposal, it is also implicated in nutrient sensing, immune cell signaling, metabolism, and membrane repair [12]. Emerging studies show that intra-lysosomal and extra-lysosomal processes govern lysosomal fusion and fission [13], exocytosis [14], positioning [15] and formation of a membrane contact site [16]. Lysosome fusion and fission influence lysosome number, size and exocytosis [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Emerging studies show that intra-lysosomal and extra-lysosomal processes govern lysosomal fusion and fission [13], exocytosis [14], positioning [15] and formation of a membrane contact site [16]. Lysosome fusion and fission influence lysosome number, size and exocytosis [13][14][15]. Furthermore, depending on cellular metabolic requirements, or activation by distinct stimuli, lysosomes mobilize to either the cell periphery or to the perinuclear region [15].…”

Section: Introductionmentioning

confidence: 99%

Lysosomal Biology and Function: Modern View of Cellular Debris Bin

Trivedi

Bartlett

Pulinilkunnil

2020

Cells

174

150

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Lysosomes are the main proteolytic compartments of mammalian cells comprising of a battery of hydrolases. Lysosomes dispose and recycle extracellular or intracellular macromolecules by fusing with endosomes or autophagosomes through specific waste clearance processes such as chaperone-mediated autophagy or microautophagy. The proteolytic end product is transported out of lysosomes via transporters or vesicular membrane trafficking. Recent studies have demonstrated lysosomes as a signaling node which sense, adapt and respond to changes in substrate metabolism to maintain cellular function. Lysosomal dysfunction not only influence pathways mediating membrane trafficking that culminate in the lysosome but also govern metabolic and signaling processes regulating protein sorting and targeting. In this review, we describe the current knowledge of lysosome in influencing sorting and nutrient signaling. We further present a mechanistic overview of intra-lysosomal processes, along with extra-lysosomal processes, governing lysosomal fusion and fission, exocytosis, positioning and membrane contact site formation. This review compiles existing knowledge in the field of lysosomal biology by describing various lysosomal events necessary to maintain cellular homeostasis facilitating development of therapies maintaining lysosomal function.

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Lysosomal size matters

Cited by 150 publications

References 205 publications

Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells

Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells

Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation

Lysosomal Biology and Function: Modern View of Cellular Debris Bin

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