bims-lysosi Biomed News
on Lysosomes and signaling
Issue of 2022–07–31
eight papers selected by
Stephanie Fernandes, Max Planck Institute for Biology of Ageing
  1. TRPML1 and TFEB, an Intimate Affair.
  2. Endo-Lysosomal Two-Pore Channels and Their Protein Partners.
  3. Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2.
  4. Activated Endolysosomal Cation Channel TRPML1 Facilitates Maturation of α-Synuclein-Containing Autophagosomes.
  5. A sphingolipid-mTORC1 nutrient-sensing pathway regulates animal development by an intestinal peroxisome relocation-based gut-brain crosstalk.
  6. Lysosomal Potassium Channels.
  7. Manganese is a physiologically relevant TORC1 activator in yeast and mammals.
  8. Beyond controlling cell size: functional analyses of S6K in tumorigenesis.
  1. Handb Exp Pharmacol. 2022 Jul 26.
    TRPML1 and TFEB, an Intimate Affair.
    Diego Luis Medina.
      Ca2+ is a universal second messenger that plays a wide variety of fundamental roles in cellular physiology. Thus, to warrant selective responses and to allow rapid mobilization upon specific stimuli, Ca2+ is accumulated in organelles to keep it at very low levels in the cytoplasm during resting conditions. Major Ca2+ storage organelles include the endoplasmic reticulum (ER), the mitochondria, and as recently demonstrated, the lysosome (Xu and Ren, Annu Rev Physiol 77:57-80, 2015). The importance of Ca2+ signaling deregulation in human physiology is underscored by its involvement in several human diseases, including lysosomal storage disorders, neurodegenerative disease and cancer (Shen et al., Nat Commun 3:731, 2012; Bae et al., J Neurosci 34:11485-11503, 2014). Recent evidence strongly suggests that lysosomal Ca2+ plays a major role in the regulation of lysosomal adaptation to nutrient availability through a lysosomal signaling pathway involving the lysosomal Ca2+ channel TRPML1 and the transcription factor TFEB, a master regulator for lysosomal function and autophagy (Sardiello et al., Science 325:473-477, 2009; Settembre et al., Science 332:1429-1433, 2011; Medina et al., Nat Cell Biol 17:288-299, 2015; Di Paola et al., Cell Calcium 69:112-121, 2018). Due to the tight relationship of this lysosomal Ca2+ channel and TFEB, in this chapter, we will focus on the role of the TRPML1/TFEB pathway in the regulation of lysosomal function and autophagy.
    Keywords:  Autophagy; Calcium signaling; Lysosome; TFEB; TRPML1
    DOI:  https://doi.org/10.1007/164_2022_603
  2. Handb Exp Pharmacol. 2022 Jul 29.
    Endo-Lysosomal Two-Pore Channels and Their Protein Partners.
    Sandip Patel, Spyros Zissimopoulos, Jonathan S Marchant.
      Two-pore channels are ion channels expressed on acidic organelles such as the various vesicles that constitute the endo-lysosomal system. They are permeable to Ca2+ and Na+ and activated by the second messenger NAADP as well as the phosphoinositide, PI(3,5)P2 and/or voltage. Here, we review the proteins that interact with these channels including recently identified NAADP receptors.
    Keywords:  Ca2+; Endosomes; Lysosomes; NAADP; Na+; PI(3,5)P2; TPCN1; TPCN2
    DOI:  https://doi.org/10.1007/164_2022_601
  3. Elife. 2022 Jul 26. pii: e75398. [Epub ahead of print]11
    Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2.
    Polina Kosillo, Kamran M Ahmed, Erin E Aisenberg, Vasiliki Karalis, Bradley M Roberts, Stephanie J Cragg, Helen S Bateup.
      The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function.
    Keywords:  TSC; dopamine neurons; mTORC1; mTORC2; mouse; neuroscience; raptor; rictor
    DOI:  https://doi.org/10.7554/eLife.75398
  4. Front Cell Neurosci. 2022 ;16 861202
    Activated Endolysosomal Cation Channel TRPML1 Facilitates Maturation of α-Synuclein-Containing Autophagosomes.
    Maike R Pollmanns, Judith Beer, Ines Rosignol, Natalia Rodriguez-Muela, Björn H Falkenburger, Elisabeth Dinter.
      Background: Protein aggregates are degraded via the autophagy-lysosome pathway and alterations in the lysosomal system leading to the accumulation of pathogenic proteins, including aggregates of α-synuclein in Parkinson's disease (PD). The importance of the endolysosomal transient receptor potential cation channel, mucolipin subfamily 1 (TRPML1) for the lysosomal function is highlighted by the fact that TRPML1 mutations cause the lysosomal storage disease mucolipidosis type IV. In this study, we investigated the mechanism by which activation of TRPML1 affects the degradation of α-synuclein. Methods: As a model of α-synuclein pathology, we expressed the pathogenic A53Tα-synuclein mutant in HEK293T cells. These cells were treated with the synthetic TRPML1 agonist ML-SA1. The amount of α-synuclein protein was determined by immunoblots. The abundance of aggregates and autolysosomal vesicles was determined by fluorescence microscopy and immunocytochemistry. Findings were confirmed by life-cell imaging and by application of ML-SA1 and the TRPML1 antagonist ML-SI3 to human dopaminergic neurons and human stem cell-derived neurons. Results: ML-SA1 reduced the percentage of HEK293T cells with α-synuclein aggregates and the amount of α-synuclein protein. The effect of ML-SA1 was blocked by pharmacological and genetic inhibition of autophagy. Consistent with TRPML function, it required the membrane lipid PI(3,5)P2, and cytosolic calcium. ML-SA1 shifted the composition of autophagosomes towards a higher fraction of mature autolysosomes, also in presence of α-synuclein. In neurons, inhibition of TRPML1 by its antagonist ML-SI3 blocked autophagosomal clearance, whereas the agonist ML-SA1 shifted the composition of a-synuclein particles towards a higher fraction of acidified particles. ML-SA1 was able to override the effect of Bafilomycin A1, which blocks the fusion of the autophagosome and lysosome and its acidification. Conclusion: These findings suggest, that activating TRPML1 with ML-SA1 facilitates clearance of α-synuclein aggregates primarily by affecting the late steps of the autophagy, i.e., by promoting autophagosome maturation. In agreement with recent work by others, our findings indicate that TRPML1 might constitute a plausible therapeutic target for PD, that warrants further validation in rodent models of α-synuclein pathology.
    Keywords:  ML-SA1; Parkinson’s disease; TRPML1; acidification; autolysosome maturation; autophagy; mucolipin-1; synuclein
    DOI:  https://doi.org/10.3389/fncel.2022.861202
  5. Cell Rep. 2022 Jul 26. pii: S2211-1247(22)00949-4. [Epub ahead of print]40(4): 111140
    A sphingolipid-mTORC1 nutrient-sensing pathway regulates animal development by an intestinal peroxisome relocation-based gut-brain crosstalk.
    Na Li, Beilei Hua, Qing Chen, Fukang Teng, Meiyu Ruan, Mengnan Zhu, Li Zhang, Yinbo Huo, Hongqin Liu, Min Zhuang, Huali Shen, Huanhu Zhu.
      The mTOR-dependent nutrient-sensing and response machinery is the central hub for animals to regulate their cellular and developmental programs. However, equivalently pivotal nutrient and metabolite signals upstream of mTOR and developmental-regulatory signals downstream of mTOR are not clear, especially at the organism level. We previously showed glucosylceramide (GlcCer) acts as a critical nutrient and metabolite signal for overall amino acid levels to promote development by activating the intestinal mTORC1 signaling pathway. Here, through a large-scale genetic screen, we find that the intestinal peroxisome is critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, GlcCer deficiency, inactive mTORC1, or prolonged starvation relocates intestinal peroxisomes closer to the apical region in a kinesin- and microtubule-dependent manner. Those apical accumulated peroxisomes further release peroxisomal-β-oxidation-derived glycolipid hormones that target chemosensory neurons and downstream nuclear hormone receptor DAF-12 to arrest the animal development. Our data illustrate a sophisticated gut-brain axis that predominantly orchestrates nutrient-sensing-dependent development in animals.
    Keywords:  C.elegans; CP: Cell biology; ascaroside; diapause; glucosylceramide; gut-brain axis; hormone; mTOR pathway; metabolism; nutrient sensing; peroxisome repositioning
    DOI:  https://doi.org/10.1016/j.celrep.2022.111140
  6. Handb Exp Pharmacol. 2022 Jul 26.
    Lysosomal Potassium Channels.
    Peng Huang, Mengnan Xu, Yi Wu, Alia Kazim Rizvi Syeda, Xian-Ping Dong.
      Lysosomes are acidic membrane-bound organelles that use hydrolytic enzymes to break down material through pathways such as endocytosis, phagocytosis, mitophagy, and autophagy. To function properly, intralysosomal environments are strictly controlled by a set of integral membrane proteins such as ion channels and transporters. Potassium ion (K+) channels are a large and diverse family of membrane proteins that control K+ flux across both the plasma membrane and intracellular membranes. In the plasma membrane, they are essential in both excitable and non-excitable cells for the control of membrane potential and cell signaling. However, our understanding of intracellular K+ channels is very limited. In this review, we summarize the recent development in studies of K+ channels in the lysosome. We focus on their characterization, potential roles in maintaining lysosomal membrane potential and lysosomal function, and pathological implications.
    Keywords:  BK channel; Lysosome; Potassium channel; TMEM175
    DOI:  https://doi.org/10.1007/164_2022_600
  7. Elife. 2022 Jul 29. pii: e80497. [Epub ahead of print]11
    Manganese is a physiologically relevant TORC1 activator in yeast and mammals.
    Raffaele Nicastro, Hélène Gaillard, Laura Zarzuela, Marie-Pierre Péli-Gulli, Elisabet Fernández-García, Mercedes Tomé, Néstor García-Rodríguez, Raúl V Durán, Claudio De Virgilio, Ralf Erik Wellinger.
      The essential biometal manganese (Mn) serves as a cofactor for several enzymes that are crucial for the prevention of human diseases. Whether intracellular Mn levels may be sensed and modulate intracellular signaling events has so far remained largely unexplored. The highly conserved target of rapamycin complex 1 (TORC1, mTORC1 in mammals) protein kinase requires divalent metal cofactors such as magnesium (Mg2+) to phosphorylate effectors as part of a homeostatic process that coordinates cell growth and metabolism with nutrient and/or growth factor availability. Here, our genetic approaches reveal that TORC1 activity is stimulated in vivo by elevated cytoplasmic Mn levels, which can be induced by loss of the Golgi-resident Mn2+ transporter Pmr1 and which depend on the natural resistance-associated macrophage protein (NRAMP) metal ion transporters Smf1 and Smf2. Accordingly, genetic interventions that increase cytoplasmic Mn2+ levels antagonize the effects of rapamycin in triggering autophagy, mitophagy, and Rtg1-Rtg3-dependent mitochondrion-to-nucleus retrograde signaling. Surprisingly, our in vitro protein kinase assays uncovered that Mn2+ activates TORC1 substantially better than Mg2+, which is primarily due to its ability to lower the Km for ATP, thereby allowing more efficient ATP coordination in the catalytic cleft of TORC1. These findings, therefore, provide both a mechanism to explain our genetic observations in yeast and a rationale for how fluctuations in trace amounts of Mn can become physiologically relevant. Supporting this notion, TORC1 is also wired to feedback control mechanisms that impinge on Smf1 and Smf2. Finally, we also show that Mn2+-mediated control of TORC1 is evolutionarily conserved in mammals, which may prove relevant for our understanding of the role of Mn in human diseases.
    Keywords:  NRAMP transporter; S. cerevisiae; TORC1; autophagy; biochemistry; chemical biology; genetics; genomics; human; manganese; mitophagy
    DOI:  https://doi.org/10.7554/eLife.80497
  8. Cell Death Dis. 2022 Jul 25. 13(7): 646
    Beyond controlling cell size: functional analyses of S6K in tumorigenesis.
    Xueji Wu, Wei Xie, Wenxuan Xie, Wenyi Wei, Jianping Guo.
      As a substrate and major effector of the mammalian target of rapamycin complex 1 (mTORC1), the biological functions of ribosomal protein S6 kinase (S6K) have been canonically assigned for cell size control by facilitating mRNA transcription, splicing, and protein synthesis. However, accumulating evidence implies that diverse stimuli and upstream regulators modulate S6K kinase activity, leading to the activation of a plethora of downstream substrates for distinct pathobiological functions. Beyond controlling cell size, S6K simultaneously plays crucial roles in directing cell apoptosis, metabolism, and feedback regulation of its upstream signals. Thus, we comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for S6K and shed light on S6K as a potential therapeutic target for cancers.
    DOI:  https://doi.org/10.1038/s41419-022-05081-4
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