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PreprintCited by 5Cell death mechanisms and regulationAquatic Ecosystems and Phytoplankton DynamicsProtist diversity and phylogeny

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Cathepsin X is a conserved cell death protein involved in algal response to environmental stress

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Mizrachi, Avia, Sadeh, Mai, Ben-Dor, Shifra, Dym, Orly, Ku, Chuan, Feldmesser, Ester, Zarfin, Amichai, Brunson, John K., Allen, Andrew E., Jinkerson, Robert E., Schatz, Daniella, Vardi, Assaf·2024·Current Biology
DOI 10.1101/2024.05.15.594278

Preprint — published as 10.1016/j.cub.2025.03.045 · Paper page

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Abstract

Phytoplankton play a crucial role in global primary production and can form vast blooms in aquatic ecosystems. Bloom demise and the rapid turnover of phytoplankton are suggested to involve programmed cell death (PCD) induced by diverse environmental stressors. However, fundamental knowledge of the PCD molecular components in algae and protists in general remains elusive. Previously, we revealed that early oxidation in the chloroplast predicted subsequent cell death or survival in isogenic subpopulations that emerged following H 2 O 2 treatment in the diatom Phaeodactylum tricornutum . Here, we performed transcriptome analysis of sorted sensitive oxidized cells and resilient reduced cells, to discover genes linked to their contrasting fates. By cross-comparison with a large-scale mutant screen in the green alga Chlamydomonas reinhardtii , we identified functionally relevant conserved PCD gene candidates, including the cysteine protease cathepsin X/Z ( CPX ). CPX mutants in P. tricornutum CPX1 and C. reinhardtii CEP12 both exhibited profound resilience to oxidative stress, supporting a conserved function in algal PCD. P. tricornutum cpx1 mutants, generated using CRISPR-Cas9, also exhibited resilience to the toxic diatom-derived infochemical cyanogen bromide. Phylogenetic and predictive structural analyses show that CPX is highly conserved in eukaryotes, and algae of the green and red lineages exhibit strong structural similarity to human cathepsin CTSZ . CPX is expressed by diverse algae across the oceans and during toxic Pseudo-nitzschia blooms, supporting its ecological importance. Elucidating PCD components in algae sheds light on the evolutionary origin of PCD in unicellular organisms, and on the cellular strategies employed by the population to cope with stressful conditions.

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Research works printed but not linked: 124

  1. 10.1126/science.281.5374.237 · DOI · Paper page
  2. 10.1073/pnas.1711842115 · DOI · Paper page
  3. 10.1126/science.1095964 · DOI · Paper page
  4. 10.1126/science.1083545 · DOI
  5. Nelson, D. M. , Tréguer, P. , Brzezinski, M. a., Leynaert, A. & Quéguiner, B. Production and dissolution of biogenic silica in the ocean: Revised global estimates, comparison with regional data and relationship to biogenic sedimentation. Global Biogeochem. Cycles 9, 359 (1995). · DOI
  6. 10.1007/BF02390423 · DOI
  7. 10.1038/nature08057 · DOI · Paper page
  8. 10.1038/s41561-017-0028-x · DOI
  9. 10.1146/annurev-marine-052913-021325 · DOI
  10. 2020, Algal blooms, Curr. Biol, 30, R1116, 10.1016/j.cub.2020.07.011 · DOI
  11. 10.1016/j.cub.2016.05.056 · DOI
  12. 10.1073/pnas.1208895109 · DOI
  13. 10.1016/S0960-9822(99)80459-X · DOI
  14. 10.1093/jxb/ern330 · DOI
  15. 10.1086/657686 · DOI
  16. 10.1038/ismej.2014.136 · DOI
  17. 2015, Programmed cell death is induced by hydrogen peroxide but not by excessive ionic stress of sodium chloride in the unicellular green alga Chlamydomonas reinhardtii, Eur. J. Phycol, 50, 422, 10.1080/09670262.2015.1070437 · DOI
  18. 10.1038/s41467-017-01300-1 · DOI
  19. 10.1093/plphys/kiad618 · DOI
  20. 2007, Viral activation and recruitment of metacaspases in the unicellular coccolithophore, Emiliania huxleyi. Proc. Natl. Acad. Sci, 104, 6049, 10.1073/pnas.0701240104 · DOI
  21. Fichman, Y. , Rowland, L. , Oliver, M. J. & Mittler, R . ROS are evolutionary conserved cell-to-cell stress signals. Proc. Natl. Acad. Sci. 120, (2023). · DOI
  22. 10.1007/978-3-030-92499-7_22 · DOI
  23. 10.1038/nrm2256 · DOI · Paper page
  24. 10.1016/j.tplants.2015.08.002 · DOI
  25. 10.1016/j.gde.2011.10.001 · DOI · Paper page
  26. Schreiber, F. et al. Phenotypic heterogeneity driven by nutrient limitation promotes growth in fluctuating environments. Nat. Microbiol. 1, 16055 (2016). · DOI
  27. 10.1038/nature21415 · DOI
  28. 10.1016/j.protis.2011.02.002 · DOI
  29. 2012, Grazer-induced chain length plasticity reduces grazing risk in a marine diatom, Limnol. Oceanogr, 57, 318, 10.4319/lo.2012.57.1.0318 · DOI
  30. 10.1073/pnas.1309345110 · DOI
  31. 2013, High throughput imaging to the diatom Cyclotella cryptica demonstrates substantial cell-to-cell variability in the rate and extent of triacylglycerol accumulation, Algal Res, 2, 244, 10.1016/j.algal.2013.03.003 · DOI
  32. Godhe, A. & Rynearson, T . The role of intraspecific variation in the ecological and evolutionary success of diatoms in changing environments. Philos. Trans. R. Soc. B Biol. Sci. 372, 20160399 (2017). · DOI
  33. 10.3389/fpls.2019.00599 · DOI
  34. 10.7554/elife.39324 · DOI · Paper page
  35. 10.1007/BF00392493 · DOI
  36. 10.1073/pnas.1015744108 · DOI
  37. 10.1111/1462-2920.14434 · DOI
  38. 10.1111/nph.16951 · DOI
  39. 10.1074/jbc.M312846200 · DOI · Paper page
  40. 10.1073/pnas.1319773111 · DOI
  41. 10.1038/s41598-018-23106-x · DOI
  42. 10.1038/s41588-022-01052-9 · DOI
  43. 10.1038/s41588-019-0370-6 · DOI
  44. 10.1534/genetics.105.052266 · DOI
  45. 10.1073/pnas.0707359105 · DOI
  46. 2019, Genome-Wide Studies of Rho5-Interacting Proteins That Are Involved in Oxidant-Induced Cell Death in Budding Yeast, G3 Genes|Genomes|Genetics, 9, 921, 10.1534/g3.118.200887 · DOI
  47. 10.1038/cddis.2011.72 · DOI
  48. 10.1016/j.biochi.2007.07.024 · DOI
  49. de Castro, M. , Bunt, G. & Wouters, F . Cathepsin B launches an apoptotic exit effort upon cell death-associated disruption of lysosomes. Cell Death Discov. 2, 16012 (2016). · DOI
  50. 10.1038/cdd.2016.34 · DOI
  51. 2018, Two proteases with caspase-3-like activity, cathepsin B and proteasome, antagonistically control ER - stress-induced programmed cell death in Arabidopsis, New Phytol, 218, 1143, 10.1111/nph.14676 · DOI
  52. Xie, Z. et al. Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways. Cell Death Dis. 14, 255 (2023). · DOI
  53. 2009, The role of cathepsin X in cell signaling, Cell Adhes. Migr, 3, 164, 10.4161/cam.3.2.7403 · DOI
  54. 2015, Intracellular signaling by cathepsin X: Molecular mechanisms and diagnostic and therapeutic opportunities in cancer, Semin. Cancer Biol, 31, 76, 10.1016/j.semcancer.2014.05.001 · DOI
  55. Mitrović, A. et al. Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy. Cell. Mol. Life Sci. 79, (2022). · DOI
  56. 10.1073/pnas.1108062109 · DOI
  57. Kordiš, D. & Turk, V . Origin and Early Diversification of the Papain Family of Cysteine Peptidases. Int. J. Mol. Sci. 24, 11761 (2023). · DOI · Paper page
  58. 10.1104/pp.112.194001 · DOI
  59. Martinez, M. & Diaz, I . The origin and evolution of plant cystatins and their target cysteine proteinases indicate a complex functional relationship. BMC Evol. Biol. 8, 198 (2008). · DOI
  60. 60. Brunson, J. K., et al. Molecular Forecasting of Domoic Acid during a Pervasive Toxic Diatom Bloom. bioRxiv (2023). · DOI
  61. 2021, Human cathepsin X/Z is a biologically active homodimer, Biochim. Biophys. Acta - Proteins Proteomics, 140567, 1869
  62. 10.1016/S0969-2126(00)00108-8 · DOI
  63. 10.1021/bi991371z · DOI
  64. 10.1021/bi002460a · DOI
  65. Campden, R. I. et al. Extracellular cathepsin Z signals through the α5 integrin and augments NLRP3 inflammasome activation. J. Biol. Chem. 298, 101459 (2022). · DOI
  66. 2022, The Ocean Gene Atlas v2.0: online exploration of the biogeography and phylogeny of plankton genes, Nucleic Acids Res, 50, W516, 10.1093/nar/gkac420 · DOI
  67. 10.1093/nar/gkj109 · DOI · Paper page
  68. 2020, A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia, Haematologica, 107, 77, 10.3324/haematol.2020.257964 · DOI
  69. 2020, Ribosomal protein S11 influences glioma response to TOP2 poisons, Oncogene, 39, 5068, 10.1038/s41388-020-1342-0 · DOI
  70. 10.1073/pnas.2010723117 · DOI
  71. Urbanek, K. et al. Cytidine Monophosphate N -Acetylneuraminic Acid Synthetase and Solute Carrier Family 35 Member A1 Are Required for Reovirus Binding and Infection. J. Virol. 95, (2020). · DOI
  72. 2015, Lysosomal cysteine peptidases – Molecules signaling tumor cell death and survival, Semin. Cancer Biol, 35, 168, 10.1016/j.semcancer.2015.08.001 · DOI
  73. 2018, Cathepsins: Proteases that are vital for survival but can also be fatal, Biomed. Pharmacother, 105, 526, 10.1016/j.biopha.2018.05.148 · DOI · Paper page
  74. 2011, Cellular senescence induced by cathepsin X downregulation, Eur. J. Cell Biol, 90, 678, 10.1016/j.ejcb.2011.03.008 · DOI
  75. Ding, X. , Zhang, C. , Chen, H. , Ren, M. & Liu, X . Cathepsins Trigger Cell Death and Regulate Radioresistance in Glioblastoma. Cells 11, (2022). · DOI
  76. 2021, Elucidation of the Algicidal Mechanism of the Marine Bacterium Pseudoruegeria sp. M32A2M Against the Harmful Alga Alexandrium catenella Based on Time-Course Transcriptome Analysis, Front. Mar. Sci., 8, 1
  77. 10.1038/cddis.2014.570 · DOI
  78. Zimmermann, A. et al. Transcriptional and epigenetic control of regulated cell death in yeast. in International Review of Cell and Molecular Biology 352, 55–82 (Elsevier Inc., 2020). · DOI
  79. 10.1146/annurev-marine-010213-135014 · DOI
  80. 10.1038/nrmicro1461 · DOI
  81. 10.1016/j.cub.2016.05.057 · DOI
  82. 10.1038/nrmicro3178 · DOI
  83. 10.1126/science.1262053 · DOI · Paper page
  84. Eisele-Bürger, A. M. et al. Calmodulin regulates protease versus co-chaperone activity of a metacaspase. Cell Rep. 42, 113372 (2023). · DOI
  85. Hill, S. M. , Hao, X. , Liu, B. & Nyström, T . Life-span extension by a metacaspase in the yeast Saccharomyces cerevisiae. Science (80-.). 344, 1389–1392 (2014). · DOI
  86. Orellana, M. V. , Pang, W. L. , Durand, P. M. , Whitehead, K. & Baliga, N. S . A Role for Programmed Cell Death in the Microbial Loop. PLoS One 8, (2013). · DOI
  87. 10.1111/j.1462-2920.2007.01257.x · DOI
  88. 2018, Programmed cell death in diazotrophs and the fate of organic matter in the western tropical South Pacific Ocean during the OUTPACE cruise, Biogeosciences, 15, 3893, 10.5194/bg-15-3893-2018 · DOI
  89. 10.3354/meps07333 · DOI
  90. 2018, Dynamics of transparent exopolymer particle production and aggregation during viral infection of the coccolithophore, Emiliania huxleyi, Environ. Microbiol, 20, 2880, 10.1111/1462-2920.14261 · DOI
  91. 10.1038/s41579-023-00975-2 · DOI
  92. 10.1371/journal.pbio.0040060 · DOI
  93. 10.1139/m62-029 · DOI
  94. 10.1111/j.1365-2818.2008.02030.x · DOI
  95. 10.1038/s41596-019-0164-4 · DOI · Paper page
  96. Kohen, R. et al. UTAP: User-friendly Transcriptome Analysis Pipeline. BMC Bioinformatics 20, 154 (2019). · DOI
  97. Martin, M . Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet.journal 17, 10 (2011). · DOI · Paper page
  98. 10.1093/bioinformatics/bts635 · DOI · Paper page
  99. 10.1093/bioinformatics/btu638 · DOI · Paper page
  100. Love, M. I. , Huber, W. & Anders, S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). · DOI · Paper page
  101. 10.1093/nar/gky1055 · DOI · Paper page
  102. 10.1093/nar/gkv1070 · DOI · Paper page
  103. 10.1093/nar/gkv1248 · DOI
  104. 10.1093/molbev/msx148. · DOI · Paper page
  105. Gschloessl, B. , Guermeur, Y. & Cock, J. M . HECTAR: A method to predict subcellular targeting in heterokonts. BMC Bioinformatics 9, 393 (2008). · DOI
  106. 10.1111/tpj.12734 · DOI
  107. Maxwell, K. & Johnson, G. N . Chlorophyll fluorescence — a practical guide. 51, 659– 668 (2000). · DOI · Paper page
  108. 10.1038/srep26159 · DOI
  109. 10.1038/nbt.2647 · DOI · Paper page
  110. 10.1038/nbt.3437 · DOI · Paper page
  111. 10.1093/nar/gky354 · DOI
  112. Rastogi, A. , Murik, O. , Bowler, C. & Tirichine, L . PhytoCRISP-Ex: a web-based and stand-alone application to find specific target sequences for CRISPR/CAS editing. BMC Bioinformatics 17, 261 (2016). · DOI
  113. 10.1093/bioinformatics/btu048 · DOI · Paper page
  114. 10.1242/jcs.00092 · DOI
  115. 10.1093/nar/gks596 · DOI
  116. 10.1186/1471-2105-10-421 · DOI · Paper page
  117. 10.1093/nar/gkz991 · DOI
  118. 10.1093/nar/gkh340 · DOI · Paper page
  119. 10.1093/sysbio/syq010 · DOI · Paper page
  120. 10.1093/nar/gkae268 · DOI
  121. 10.1093/nar/16.22.10881 · DOI
  122. 2020, Improved protein structure prediction using potentials from deep learning, Nature, 577, 706, 10.1038/s41586-019-1923-7 · DOI · Paper page
  123. 10.1093/nar/gkac278 · DOI
  124. 10.1093/nar/30.1.207 · DOI · Paper page

Metadata

Authors
Mizrachi, A., Sadeh, M., Ben-Dor, S., Dym, O., Ku, C., Feldmesser, E., Zarfin, A., Brunson, J. K., Allen, A. E., Jinkerson, R. E., Schatz, D., & Vardi, A.
Affiliations
  • Weizmann Institute of Science (IL)
  • J. Craig Venter Institute (US)
  • University of California, Riverside (US)
Corresponding author
Vardi, Assaf
ORCID
Venue
Current Biology
Publisher
openRxiv
Published
2024-05-15
Volume
35
Issue
10
Pages
2240-2255.e6
ISSN
0960-9822 (ISSN-L)
DOI
10.1101/2024.05.15.594278
OpenAlex
W4409412786
Cited by
5
References
1
Citations by year
2026: 3 · 2025: 2
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Current Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Israel Science Foundation (749/24, 1972/20)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Physical Sciences › Environmental Science › Environmental Chemistry › Aquatic Ecosystems and Phytoplankton Dynamics
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Protist diversity and phylogeny
Keywords
cathepsin X, programmed cell death, algal cell death, oxidative stress, Phaeodactylum tricornutum, Chlamydomonas reinhardtii, cysteine protease, phytoplankton, cellular heterogeneity, semiochemicals, comparative transcriptomics
MeSH terms
Cathepsins, Phylogeny, Chlamydomonas reinhardtii, Apoptosis, Diatoms, Oxidative Stress, Algal Proteins

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