bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2023‒10‒29
thirteen papers selected by
Lakesh Kumar, BITS Pilani
  1. A conserved complex of microneme proteins mediates rhoptry discharge in Toxoplasma.
  2. An updated review of chemical compounds with anti-Toxoplasma gondii activity.
  3. The protein phosphatase PPKL is a key regulator of daughter parasite development in Toxoplasma gondii.
  4. mRNA cap-binding protein eIF4E1 is a novel regulator of Toxoplasma gondii latency.
  5. Functional Characterization of Eight Zinc Finger Motif-Containing Proteins in Toxoplasma gondii Type I RH Strain Using the CRISPR-Cas9 System.
  6. Acetyl-CoA metabolism as a therapeutic target for cancer.
  7. The multifaceted roles of Myb domain-containing proteins in apicomplexan parasites.
  8. A patatin-like phospholipase is important for mitochondrial function in malaria parasites.
  9. In Silico Vaccine Design and Expression of the Multi-Component Protein Candidate against the Toxoplasma gondii Parasite from MIC13, GRA1, and SAG1 Antigens.
  10. The interdependence of isoprenoid synthesis and apicoplast biogenesis in malaria parasites.
  11. The P. falciparum alternative histones Pf H2A.Z and Pf H2B.Z are dynamically acetylated and antagonized by PfSir2 histone deacetylases at heterochromatin boundaries.
  12. The Roles of Histone Deacetylases in the Regulation of Ovarian Cancer Metastasis.
  13. Nutrient-regulated control of lysosome function by signaling lipid conversion.
  1. EMBO J. 2023 Oct 27. e113155
    A conserved complex of microneme proteins mediates rhoptry discharge in Toxoplasma.
    Dylan Valleau, Saima M Sidik, Luiz C Godoy, Yamilex Acevedo-Sánchez, Charisse Flerida A Pasaje, My-Hang Huynh, Vern B Carruthers, Jacquin C Niles, Sebastian Lourido.
      Apicomplexan parasites discharge specialized organelles called rhoptries upon host cell contact to mediate invasion. The events that drive rhoptry discharge are poorly understood, yet essential to sustain the apicomplexan parasitic life cycle. Rhoptry discharge appears to depend on proteins secreted from another set of organelles called micronemes, which vary in function from allowing host cell binding to facilitation of gliding motility. Here we examine the function of the microneme protein CLAMP, which we previously found to be necessary for Toxoplasma gondii host cell invasion, and demonstrate its essential role in rhoptry discharge. CLAMP forms a distinct complex with two other microneme proteins, the invasion-associated SPATR, and a previously uncharacterized protein we name CLAMP-linked invasion protein (CLIP). CLAMP deficiency does not impact parasite adhesion or microneme protein secretion; however, knockdown of any member of the CLAMP complex affects rhoptry discharge. Phylogenetic analysis suggests orthologs of the essential complex components, CLAMP and CLIP, are ubiquitous across apicomplexans. SPATR appears to act as an accessory factor in Toxoplasma, but despite incomplete conservation is also essential for invasion during Plasmodium falciparum blood stages. Together, our results reveal a new protein complex that mediates rhoptry discharge following host-cell contact.
    Keywords:  CLAMP; Toxoplasma; apicomplexan; invasion; rhoptry; secretion
    DOI:  https://doi.org/10.15252/embj.2022113155
  2. Eur J Med Chem. 2023 Oct 16. pii: S0223-5234(23)00852-8. [Epub ahead of print]262 115885
    An updated review of chemical compounds with anti-Toxoplasma gondii activity.
    Juan B Rodriguez, Sergio H Szajnman.
      The opportunistic apicomplexan parasite Toxoplasma gondii is the etiologic agent for toxoplasmosis, which can infect a widespread range of hosts, particularly humans and warm-blooded animals. The present chemotherapy to treat or prevent toxoplasmosis is deficient and is based on diverse drugs such as atovaquone, trimethoprim, spiramycine, which are effective in acute toxoplasmosis. Therefore, a safe chemotherapy is required for toxoplasmosis considering that its responsible agent, T. gondii, provokes severe illness and death in pregnant women and immunodeficient patients. A certain disadvantage of the available treatments is the lack of effectiveness against the tissue cyst of the parasite. A safe chemotherapy to combat toxoplasmosis should be based on the metabolic differences between the parasite and the mammalian host. This article covers different relevant molecular targets to combat this disease including the isoprenoid pathway (farnesyl diphosphate synthase, squalene synthase), dihydrofolate reductase, calcium-dependent protein kinases, histone deacetylase, mitochondrial electron transport chain, etc.
    Keywords:  Calcium-dependent protein kinases; Dihydrofolate reductase; Farnesyl diphosphate synthase; Mitochondrial electron transport chain; Squalene synthase; Toxoplasma gondii; Toxoplasma gondii adenosine kinase; Toxoplasmosis
    DOI:  https://doi.org/10.1016/j.ejmech.2023.115885
  3. mBio. 2023 Oct 25. e0225423
    The protein phosphatase PPKL is a key regulator of daughter parasite development in Toxoplasma gondii.
    Chunlin Yang, Emma H Doud, Emily Sampson, Gustavo Arrizabalaga.
      Apicomplexan parasites, including Toxoplasma gondii, encode many plant-like proteins, which play significant roles and present attractive targets for drug development. In this study, we have characterized the plant-like protein phosphatase PPKL, which is unique to the parasite and absent in its mammalian host. We have shown that its localization changes as the parasite divides. In non-dividing parasites, it is present in the cytoplasm, nucleus, and preconoidal region. As the parasite begins division, PPKL is enriched in the preconoidal region and the cortical cytoskeleton of nascent parasites. Later in the division, PPKL is present in the basal complex ring. Conditional knockdown of PPKL showed that it is essential for parasite propagation. Moreover, parasites lacking PPKL exhibit uncoupling of division, with normal DNA duplication but severe defects in forming daughter parasites. While PPKL depletion does not impair the duplication of centrosomes, it affects the stability of cortical microtubules. Both co-immunoprecipitation and proximity labeling identified the kinase DYRK1 as a potential functional partner of PPKL. Complete knockout of DYRK1 causes parasites to exhibit division defects with predominantly asynchronous divisions. Global phosphoproteomics analysis revealed a significant increase in phosphorylation of the microtubule-associated protein SPM1 in PPKL-depleted parasites, suggesting that PPKL regulates cortical microtubules by mediating the phosphorylation state of SPM1. More importantly, the phosphorylation of cell cycle-associated kinase Crk1, a known regulator of daughter cell assembly, is altered in PPKL-depleted parasites. Thus, we propose that PPKL regulates daughter parasite development by influencing the Crk1-dependent signaling pathway. IMPORTANCE Toxoplasma gondii can cause severe disease in immunocompromised or immunosuppressed patients and during congenital infections. Treating toxoplasmosis presents enormous challenges since the parasite shares many biological processes with its mammalian hosts, which results in significant side effects with current therapies. Consequently, proteins that are essential and unique to the parasite represent favorable targets for drug development. Interestingly, Toxoplasma, like other members of the phylum Apicomplexa, has numerous plant-like proteins, many of which play crucial roles and do not have equivalents in the mammalian host. In this study, we found that the plant-like protein phosphatase PPKL appears to be a key regulator of daughter parasite development. With the depletion of PPKL, the parasite shows severe defects in forming daughter parasites. This study provides novel insights into the understanding of parasite division and offers a new potential target for the development of antiparasitic drugs.
    Keywords:  Crk1; DYRK1; PPKL; SPM1; Toxoplasma; cell cycle; division; phosphatase; phosphorylation
    DOI:  https://doi.org/10.1128/mbio.02254-23
  4. bioRxiv. 2023 Oct 09. pii: 2023.10.09.561274. [Epub ahead of print]
    mRNA cap-binding protein eIF4E1 is a novel regulator of Toxoplasma gondii latency.
    Michael J Holmes, Matheus S Bastos, Vishakha Dey, Vanessa Severo, Ronald C Wek, William J Sullivan.
      The protozoan parasite Toxoplasma gondii causes serious opportunistic disease due to its ability to persist in patients as latent tissue cysts. The molecular mechanisms coordinating conversion between proliferative parasites (tachyzoites) and dormant cysts (bradyzoites) are not fully understood. We previously showed that phosphorylation of eIF2α accompanies bradyzoite formation, suggesting that this clinically relevant process involves regulation of mRNA translation. In this study, we investigated the composition and role of eIF4F multi-subunit complexes in translational control. Using CLIPseq, we find that the cap-binding subunit, eIF4E1, localizes to the 5'-end of all tachyzoite mRNAs, many of which show evidence of stemming from heterogenous transcriptional start sites. We further show that eIF4E1 operates as the predominant cap-binding protein in two distinct eIF4F complexes. Using genetic and pharmacological approaches, we found that eIF4E1 deficiency triggers efficient spontaneous formation of bradyzoites without stress induction. Consistent with this result, we also show that stress-induced bradyzoites exhibit reduced eIF4E1 expression. Overall, our findings establish a novel role for eIF4F in translational control required for parasite latency and microbial persistence.Significance: Toxoplasma gondii is an opportunistic pathogen of importance to global human and animal health. There are currently no chemotherapies targeting the encysted form of the parasite. Consequently, a better understanding of the mechanisms controlling encystation are required. Here we show that the mRNA cap-binding protein, eIF4E1, is involved in regulating the encystation process. Encysted parasites reduce eIF4E1 levels and depletion of eIF4E1 decreases the translation of ribosome-associated machinery and drives Toxoplasma encystation. Together, these data reveal a new layer of mRNA translational control that regulates parasite encystation and latency.
    DOI:  https://doi.org/10.1101/2023.10.09.561274
  5. Pathogens. 2023 Oct 11. pii: 1232. [Epub ahead of print]12(10):
    Functional Characterization of Eight Zinc Finger Motif-Containing Proteins in Toxoplasma gondii Type I RH Strain Using the CRISPR-Cas9 System.
    Jin Gao, Xiao-Jing Wu, Xiao-Nan Zheng, Ting-Ting Li, Yong-Jie Kou, Xin-Cheng Wang, Meng Wang, Xing-Quan Zhu.
      The Zinc finger protein (ZFP) family is widely distributed in eukaryotes and interacts with DNA, RNA, and various proteins to participate in many molecular processes. In the present study, the biological functions of eight ZFP genes in the lytic cycle and the pathogenicity of Toxoplasma gondii were examined using the CRISPR-Cas9 system. Immunofluorescence showed that four ZFPs (RH248270-HA, RH255310-HA, RH309200-HA, and RH236640-HA) were localized in the cytoplasm, and one ZFP (RH273150-HA) was located in the nucleus, while the expression level of RH285190-HA, RH260870-HA, and RH248450-HA was undetectable. No significant differences were detected between seven RHΔzfp strains (RHΔ285190, RHΔ248270, RHΔ260870, RHΔ255310, RHΔ309200, RHΔ248450, and RHΔ236640) and the wild-type (WT) strain in the T. gondii lytic cycle, including plaque formation, invasion, intracellular replication, and egress, as well as in vitro virulence (p > 0.05). However, the RHΔ273150 strain exhibited significantly lower replication efficiency compared to the other seven RHΔzfp strains and the WT strain, while in vivo virulence in mice was not significantly affected. Comparative expression analysis of the eight zfp genes indicates that certain genes may have essential functions in the sexual reproductive stage of T. gondii. Taken together, these findings expand our current understanding of the roles of ZFPs in T. gondii.
    Keywords:  CRISPR-Cas9; Toxoplasma gondii; replication; toxoplasmosis; zinc finger protein
    DOI:  https://doi.org/10.3390/pathogens12101232
  6. Biomed Pharmacother. 2023 Oct 19. pii: S0753-3322(23)01539-1. [Epub ahead of print]168 115741
    Acetyl-CoA metabolism as a therapeutic target for cancer.
    Guo Chen, Banghe Bao, Yang Cheng, Minxiu Tian, Jiyu Song, Liduan Zheng, Qiangsong Tong.
      Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves as a key hub for the biosynthesis of fatty acids and isoprenoids, but also serves as a signaling substrate for acetylation reactions in post-translational modification of proteins, which is crucial for the epigenetic inheritance of cells. Acetyl-CoA links lipid metabolism with histone acetylation to create a more intricate regulatory system that affects the growth, aggressiveness, and drug resistance of malignancies such as glioblastoma, breast cancer, and hepatocellular carcinoma. These fascinating advances in the knowledge of acetyl-CoA metabolism during carcinogenesis and normal physiology have raised interest regarding its modulation in malignancies. In this review, we provide an overview of the regulation and cancer relevance of main metabolic pathways in which acetyl-CoA participates. We also summarize the role of acetyl-CoA in the metabolic reprogramming and stress regulation of cancer cells, as well as medical application of inhibitors targeting its dysregulation in therapeutic intervention of cancers.
    Keywords:  Acetyl-coenzyme A metabolism; Cancer progression; Cancer therapy; Metabolic reprogramming; Protein acetylation
    DOI:  https://doi.org/10.1016/j.biopha.2023.115741
  7. Curr Opin Microbiol. 2023 Oct 20. pii: S1369-5274(23)00132-7. [Epub ahead of print]76 102395
    The multifaceted roles of Myb domain-containing proteins in apicomplexan parasites.
    Dominic Schwarz, Sebastian Lourido.
      Apicomplexan parasites are a large and diverse clade of protists responsible for significant diseases of humans and animals. Central to the ability of these parasites to colonize their host and evade immune responses is an expanded repertoire of gene-expression programs that requires the coordinated action of complex transcriptional networks. DNA-binding proteins and chromatin regulators are essential orchestrators of apicomplexan gene expression that often act in concert. Although apicomplexan genomes encode various families of putative DNA-binding proteins, most remain functionally and mechanistically unexplored. This review highlights the versatile role of myeloblastosis (Myb) domain-containing proteins in apicomplexan parasites as transcription factors and chromatin regulators. We explore the diversity of Myb domain structure and use phylogenetic analysis to identify common features across the phylum. This provides a framework to discuss functional heterogeneity and regulation of Myb domain-containing proteins particularly emphasizing their role in parasite differentiation.
    DOI:  https://doi.org/10.1016/j.mib.2023.102395
  8. mBio. 2023 Oct 26. e0171823
    A patatin-like phospholipase is important for mitochondrial function in malaria parasites.
    Emma Pietsch, Abhinay Ramaprasad, Sabrina Bielfeld, Yvonne Wohlfarter, Bohumil Maco, Korbinian Niedermüller, Louisa Wilcke, Joachim Kloehn, Markus A Keller, Dominique Soldati-Favre, Michael J Blackman, Tim-Wolf Gilberger, Paul-Christian Burda.
      Plasmodium parasites rely on a functional electron transport chain (ETC) within their mitochondrion for proliferation, and compounds targeting mitochondrial functions are validated antimalarials. Here, we localize Plasmodium falciparum patatin-like phospholipase 2 (PfPNPLA2, PF3D7_1358000) to the mitochondrion and reveal that disruption of the PfPNPLA2 gene impairs asexual replication. PfPNPLA2-null parasites are hypersensitive to proguanil and inhibitors of the mitochondrial ETC, including atovaquone. In addition, PfPNPLA2-deficient parasites show reduced mitochondrial respiration and reduced mitochondrial membrane potential, indicating that disruption of PfPNPLA2 leads to a defect in the parasite ETC. Lipidomic analysis of the mitochondrial phospholipid cardiolipin (CL) reveals that loss of PfPNPLA2 is associated with a moderate shift toward shorter-chained and more saturated CL species, implying a contribution of PfPNPLA2 to CL remodeling. PfPNPLA2-deficient parasites display profound defects in gametocytogenesis, underlining the importance of a functional mitochondrial ETC during both the asexual and sexual development of the parasite. IMPORTANCE For their proliferation within red blood cells, malaria parasites depend on a functional electron transport chain (ETC) within their mitochondrion, which is the target of several antimalarial drugs. Here, we have used gene disruption to identify a patatin-like phospholipase, PfPNPLA2, as important for parasite replication and mitochondrial function in Plasmodium falciparum. Parasites lacking PfPNPLA2 show defects in their ETC and become hypersensitive to mitochondrion-targeting drugs. Furthermore, PfPNPLA2-deficient parasites show differences in the composition of their cardiolipins, a unique class of phospholipids with key roles in mitochondrial functions. Finally, we demonstrate that parasites devoid of PfPNPLA2 have a defect in gametocyte maturation, underlining the importance of a functional ETC for parasite transmission to the mosquito vector.
    Keywords:  cardiolipin; electron transport chain; malaria; mitochondrion; patatin-like phospholipase
    DOI:  https://doi.org/10.1128/mbio.01718-23
  9. Iran J Parasitol. 2023 Jul-Sep;18(3):18(3): 301-312
    In Silico Vaccine Design and Expression of the Multi-Component Protein Candidate against the Toxoplasma gondii Parasite from MIC13, GRA1, and SAG1 Antigens.
    Zahra Hosseininejad, Ahmad Daryani, Mahdi Fasihi-Ramandi, Hossein Asgarian-Omran, Reza Valadan, Tooran Nayeri, Samira Dodangeh, Shahabeddin Sarvi.
      Background: We aimed to design a B and T cell recombinant protein vaccine of Toxoplasma gondii with in silico approach. MIC13 plays an important role in spreading the parasite in the host body. GRA1 causes the persistence of the parasite in the parasitophorous vacuole. SAG1 plays a role in host-cell adhesion and cell invasion.Methods: Amino acid positions 73-272 from MIC13, 71-190 from GRA1, and 101-300 from SAG1 were selected and joined with linker A(EAAAK)A. The structures, antigenicity, allergenicity, physicochemical properties, as well as codon optimization and mRNA structure of this recombinant protein called MGS1, were predicted using bioinformatics servers. The designed structure was synthesized and then cloned in pET28a (+) plasmid and transformed into Escherichia coli BL21.
    Results: The number of amino acids in this antigen was 555, and its antigenicity was estimated to be 0.6340. SDS-PAGE and Western blotting confirmed gene expression and successful production of the protein with a molecular weight of 59.56kDa. This protein will be used in our future studies as an anti-Toxoplasma vaccine candidate in animal models.
    Conclusion: In silico methods are efficient for understanding information about proteins, selecting immunogenic epitopes, and finally producing recombinant proteins, as well as reducing the time and cost of vaccine design.
    Keywords:  In silico; Toxoplasma gondii; Vaccine
    DOI:  https://doi.org/10.18502/ijpa.v18i3.13753
  10. PLoS Pathog. 2023 Oct;19(10): e1011713
    The interdependence of isoprenoid synthesis and apicoplast biogenesis in malaria parasites.
    Megan Okada, Paul A Sigala.
      Isoprenoid precursor synthesis is an ancient and fundamental function of plastid organelles and a critical metabolic activity of the apicoplast in Plasmodium malaria parasites [1-3]. Over the past decade, our understanding of apicoplast properties and functions has increased enormously [4], due in large part to our ability to rescue blood-stage parasites from apicoplast-specific dysfunctions by supplementing cultures with isopentenyl pyrophosphate (IPP), a key output of this organelle [5,6]. In this Pearl, we explore the interdependence between isoprenoid metabolism and apicoplast biogenesis in P. falciparum and highlight critical future questions to answer.
    DOI:  https://doi.org/10.1371/journal.ppat.1011713
  11. mBio. 2023 Oct 26. e0201423
    The P. falciparum alternative histones Pf H2A.Z and Pf H2B.Z are dynamically acetylated and antagonized by PfSir2 histone deacetylases at heterochromatin boundaries.
    Suffian Azizan, Shamista A Selvarajah, Jingyi Tang, Myriam D Jeninga, Danae Schulz, Kapil Pareek, Tamara Herr, Karen P Day, Tania F De Koning-Ward, Michaela Petter, Michael F Duffy.
      The Plasmodium falciparum alternative histones Pf H2A.Z and Pf H2B.Z are enriched in the same nucleosomes in intergenic euchromatin but depleted from heterochromatin. They occupy most promoters but are only dynamically associated with expression at var genes. In other organisms, acetylation of H2A.Z is important for its functions in gene expression and chromatin structure. Here, we show that acetylated Pf H2A.Z and Pf H2B.Z are dynamically associated with gene expression at promoters. In addition, acetylated Pf H2A.Z and Pf H2B.Z are antagonized by the sirtuin class III histone deacetylases (HDAC) PfSir2A and B at heterochromatin boundaries and encroach upon heterochromatin in parasites lacking PfSir2A or B. However, the majority of acetylated Pf H2A.Z and Pf H2B.Z are deacetylated by class I or II HDACs. Acetylated Pf H2A.Z and Pf H2B.Z are also dynamically associated with promoter activity of both canonical upstream var gene promoters and var gene introns. These findings suggest that both acetylated Pf H2A.Z and Pf H2B.Z play critical roles in gene expression and contribute to maintenance of chromatin structure at the boundaries of subtelomeric, facultative heterochromatin, critical for the variegated expression of genes that enable rapid adaptation to altered host environments.IMPORTANCEThe malaria parasite Plasmodium falciparum relies on variant expression of members of multi-gene families as a strategy for environmental adaptation to promote parasite survival and pathogenesis. These genes are located in transcriptionally silenced DNA regions. A limited number of these genes escape gene silencing, and switching between them confers variant fitness on parasite progeny. Here, we show that PfSir2 histone deacetylases antagonize DNA-interacting acetylated alternative histones at the boundaries between active and silent DNA. This finding implicates acetylated alternative histones in the mechanism regulating P. falciparum variant gene silencing and thus malaria pathogenesis. This work also revealed that acetylation of alternative histones at promoters is dynamically associated with promoter activity across the genome, implicating acetylation of alternative histones in gene regulation genome wide. Understanding mechanisms of gene regulation in P. falciparum may aid in the development of new therapeutic strategies for malaria, which killed 619,000 people in 2021.
    Keywords:  chromatin; epigenetics; malaria; regulation of gene expression; variant histones
    DOI:  https://doi.org/10.1128/mbio.02014-23
  12. Int J Mol Sci. 2023 Oct 11. pii: 15066. [Epub ahead of print]24(20):
    The Roles of Histone Deacetylases in the Regulation of Ovarian Cancer Metastasis.
    Long Xu, Xiaoyu Yan, Jian Wang, Yuanxin Zhao, Qingqing Liu, Jiaying Fu, Xinyi Shi, Jing Su.
      Ovarian cancer is the most lethal gynecologic malignancy, and metastasis is the major cause of death in patients with ovarian cancer, which is regulated by the coordinated interplay of genetic and epigenetic mechanisms. Histone deacetylases (HDACs) are enzymes that can catalyze the deacetylation of histone and some non-histone proteins and that are involved in the regulation of a variety of biological processes via the regulation of gene transcription and the functions of non-histone proteins such as transcription factors and enzymes. Aberrant expressions of HDACs are common in ovarian cancer. Many studies have found that HDACs are involved in regulating a variety of events associated with ovarian cancer metastasis, including cell migration, invasion, and the epithelial-mesenchymal transformation. Herein, we provide a brief overview of ovarian cancer metastasis and the dysregulated expression of HDACs in ovarian cancer. In addition, we discuss the roles of HDACs in the regulation of ovarian cancer metastasis. Finally, we discuss the development of compounds that target HDACs and highlight their importance in the future of ovarian cancer therapy.
    Keywords:  histone deacetylase inhibitors; histone deacetylases; metastasis; ovarian cancer
    DOI:  https://doi.org/10.3390/ijms242015066
  13. Cell. 2023 Oct 18. pii: S0092-8674(23)01081-4. [Epub ahead of print]
    Nutrient-regulated control of lysosome function by signaling lipid conversion.
    Michael Ebner, Dmytro Puchkov, Orestes López-Ortega, Pathma Muthukottiappan, Yanwei Su, Christopher Schmied, Silke Zillmann, Iryna Nikonenko, Jochen Koddebusch, Gillian L Dornan, Max T Lucht, Vonda Koka, Wonyul Jang, Philipp Alexander Koch, Alexander Wallroth, Martin Lehmann, Britta Brügger, Mario Pende, Dominic Winter, Volker Haucke.
      Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated in response to cellular nutrient status is poorly understood. We show here that lysosome morphology and function are reversibly controlled by a nutrient-regulated signaling lipid switch that triggers the conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active and static mTORC1-inactive degradative lysosomes clustered at the cell center. Starvation-triggered relocalization of phosphatidylinositol 4-phosphate (PI(4)P)-metabolizing enzymes reshapes the lysosomal surface proteome to facilitate lysosomal proteolysis and to repress mTORC1 signaling. Concomitantly, lysosomal phosphatidylinositol 3-phosphate (PI(3)P), which marks motile signaling-active lysosomes in the cell periphery, is erased. Interference with this PI(3)P/PI(4)P lipid switch module impairs the adaptive response of cells to altering nutrient supply. Our data unravel a key function for lysosomal phosphoinositide metabolism in rewiring organellar membrane dynamics in response to cellular nutrient status.
    Keywords:  catabolism; functional proteomics; live correlative light and electron microscopy; lysosomes; mTOR; myotubularin; nutrient signaling; nutrients; phosphoinositides
    DOI:  https://doi.org/10.1016/j.cell.2023.09.027
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