Affinage

CARS1

Cysteine--tRNA ligase, cytoplasmic · UniProt P49589

Length
748 aa
Mass
85.5 kDa
Annotated
2026-06-09
100 papers in source corpus 2 papers cited in narrative 2 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CARS1 (cysteinyl-tRNA synthetase) operates beyond canonical aminoacylation as a cysteine-responsive node coupling cysteine availability to cell survival and ferroptotic death (PMID:26184909, PMID:34472622). Under cysteine deprivation, CARS1 acts as a cysteine sensor: cysteine normally inhibits its interaction with AMPKγ2, and when cysteine is absent this inhibition is relieved, allowing CARS1 to bind AMPKγ2 and recruit CaMKK2, driving CaMKK2-dependent phosphorylation and activation of AMPK to sustain cell survival; blocking this axis under cysteine-deficient conditions causes cell death (PMID:34472622). Independently, loss of CARS1 confers resistance to ferroptosis triggered by cystine deprivation, acting upstream of the transsulfuration pathway — CARS1 knockdown induces cystathionine accumulation and serine biosynthesis/transsulfuration genes and prevents lipid ROS accumulation without altering iron homeostasis, and inhibiting transsulfuration restores ferroptosis sensitivity (PMID:26184909). No structural model or in vitro reconstitution of these activities has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2015 High

    Whether CARS1 contributes to cell death regulation was unknown; this work established it as a determinant of ferroptosis sensitivity acting upstream of the transsulfuration pathway.

    Evidence Genome-wide siRNA screen with targeted knockdown, lipid ROS and iron assays, metabolite profiling, and pharmacological transsulfuration inhibition in erastin-treated cells

    PMID:26184909

    Open questions at the time
    • Molecular mechanism by which CARS1 loss induces transsulfuration genes not defined
    • Whether the effect depends on aminoacylation activity not tested
    • No structural or biochemical characterization of the regulatory step
  2. 2021 Medium

    How cysteine availability is sensed to control survival signaling was unclear; this work showed CARS1 is a cysteine sensor that, when cysteine is absent, scaffolds AMPKγ2 and CaMKK2 to activate AMPK.

    Evidence Reciprocal co-immunoprecipitation and binding assays, cysteine supplementation/deprivation, AMPK phosphorylation assays, and loss-of-function viability assays

    PMID:34472622

    Open questions at the time
    • No in vitro reconstitution or structural validation of the cysteine-regulated CARS1–AMPKγ2 interaction
    • Direct cysteine-binding site on CARS1 not mapped
    • Relationship between the AMPK survival axis and the ferroptosis/transsulfuration role not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CARS1's aminoacylation function relates mechanistically to its cysteine-sensing and ferroptosis-regulatory roles remains unresolved.
  • Whether tRNA charging activity is required for either non-canonical function is untested
  • No structural basis for cysteine sensing
  • Connection between AMPK survival signaling and transsulfuration-dependent ferroptosis resistance unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0140299 molecular sensor activity 1
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-5357801 Programmed Cell Death 1
Partners
CAMKK2PRKAG2

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Loss of CARS (cysteinyl-tRNA synthetase) suppresses ferroptosis induced by cystine deprivation (erastin treatment). Knockdown of CARS prevented induction of lipid reactive oxygen species without altering iron homeostasis, and led to accumulation of cystathionine and upregulation of genes associated with serine biosynthesis and transsulfuration. Inhibition of the transsulfuration pathway resensitized CARS-knockdown cells to erastin, placing CARS upstream of the transsulfuration pathway in the ferroptosis resistance mechanism. Genome-wide siRNA screen, siRNA knockdown, cell death assays, lipid ROS measurement, iron homeostasis assays, metabolite profiling (cystathionine accumulation), gene expression analysis, pharmacological inhibition of transsulfuration pathway Cell death and differentiation High 26184909
2021 CARS (cysteinyl-tRNA synthetase) acts as a cysteine sensor that, under cysteine-deficient conditions, binds to AMPKγ2 and recruits CaMKK2 to activate AMPK. Cysteine itself inhibits the CARS–AMPKγ2 interaction; when cysteine is absent, this inhibition is relieved, allowing CARS to mediate binding of AMPK to CaMKK2, resulting in CaMKK2-dependent phosphorylation and activation of AMPK. Blocking AMPK activation under cysteine-deficient conditions led to cell death, establishing this cysteine-CARS-CaMKK2-AMPKγ2 axis as a cell survival mechanism under nutrient deprivation. Co-immunoprecipitation (CARS with AMPKγ2 and CaMKK2), direct binding assays, cysteine supplementation/deprivation experiments, AMPK phosphorylation assays, siRNA/genetic loss-of-function, cell viability assays The EMBO journal Medium 34472622

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 TRUCKs: the fourth generation of CARs. Expert opinion on biological therapy 575 25985798
2014 Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 501 24578504
2015 Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer discovery 408 26503962
2015 Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell death and differentiation 398 26184909
2014 Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunological reviews 300 24329791
2018 Universal CARs, universal T cells, and universal CAR T cells. Journal of hematology & oncology 244 30482221
2018 CARs versus BiTEs: A Comparison between T Cell-Redirection Strategies for Cancer Treatment. Cancer discovery 188 30012854
2017 Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains. Journal of immunology (Baltimore, Md. : 1950) 159 29288199
2022 KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nature medicine 150 36175679
2016 Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy. Annual review of pharmacology and toxicology 122 26738472
2018 Driving CARs on the uneven road of antigen heterogeneity in solid tumors. Current opinion in immunology 115 29554494
2020 Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells. Cellular & molecular immunology 113 32451454
2011 Perfluoroalkyl compounds in dust from Asian, Australian, European, and North American homes and UK cars, classrooms, and offices. Environment international 106 20810169
2018 Nanobody Based Dual Specific CARs. International journal of molecular sciences 104 29385713
2002 Polyvalent cation receptor proteins (CaRs) are salinity sensors in fish. Proceedings of the National Academy of Sciences of the United States of America 99 12093923
2017 Carboxylic acid reductase enzymes (CARs). Current opinion in chemical biology 94 29127833
2014 NKG2D CARs as cell therapy for cancer. Cancer journal (Sudbury, Mass.) 89 24667963
2021 Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs. Nature 88 34732890
2012 A sensitivity scale for targeting T cells with chimeric antigen receptors (CARs) and bispecific T-cell Engagers (BiTEs). Oncoimmunology 88 23162754
2019 Engineering switchable and programmable universal CARs for CAR T therapy. Journal of hematology & oncology 83 31272471
2017 CARs: Synthetic Immunoreceptors for Cancer Therapy and Beyond. Trends in molecular medicine 82 28416139
2016 Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. Current opinion in immunology 73 26963133
2014 CD28z CARs and armored CARs. Cancer journal (Sudbury, Mass.) 73 24667958
2011 Raman spectroscopy and CARS microscopy of stem cells and their derivatives. Journal of Raman spectroscopy : JRS 70 22319014
2017 Current modalities in cancer immunotherapy: Immunomodulatory antibodies, CARs and vaccines. Pharmacology & therapeutics 69 28322974
2014 Shedding new light on lipid functions with CARS and SRS microscopy. Biochimica et biophysica acta 67 24576891
2018 Driving cars to the clinic for solid tumors. Gene therapy 64 29880908
2016 Quantitative imaging of lipids in live mouse oocytes and early embryos using CARS microscopy. Development (Cambridge, England) 64 27151947
2023 Targeting of intracellular oncoproteins with peptide-centric CARs. Nature 60 37938771
2015 Smart CARs engineered for cancer immunotherapy. Current opinion in oncology 58 26352543
2020 Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs). Cells 57 32013131
2023 Synapse-tuned CARs enhance immune cell anti-tumor activity. Nature biotechnology 55 36732477
2021 The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains. Molecular therapy : the journal of the American Society of Gene Therapy 55 34274536
2017 Driving better and safer HER2-specific CARs for cancer therapy. Oncotarget 52 28977984
2018 PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts. Molecular therapy : the journal of the American Society of Gene Therapy 51 29861327
2016 TriKEs and BiKEs join CARs on the cancer immunotherapy highway. Human vaccines & immunotherapeutics 50 27322989
2015 Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone. Cancer immunology, immunotherapy : CII 50 26515978
2021 TCR-like CARs and TCR-CARs targeting neoepitopes: an emerging potential. Cancer gene therapy 49 33654227
2020 Programmable and multi-targeted CARs: a new breakthrough in cancer CAR-T cell therapy. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 49 32997278
2019 T Cell-Redirecting Strategies to 'STAb' Tumors: Beyond CARs and Bispecific Antibodies. Trends in immunology 49 30827461
2021 The antigen-binding moiety in the driver's seat of CARs. Medicinal research reviews 48 34028069
2019 Conventional CARs versus modular CARs. Cancer immunology, immunotherapy : CII 43 31542798
2017 Antigen-specific regulatory T cells: are police CARs the answer? Translational research : the journal of laboratory and clinical medicine 41 28688236
2023 Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility. Journal of translational medicine 39 36922828
2024 Integration of ζ-deficient CARs into the CD3ζ gene conveys potent cytotoxicity in T and NK cells. Blood 37 38493479
2020 Structure-guided engineering of the affinity and specificity of CARs against Tn-glycopeptides. Proceedings of the National Academy of Sciences of the United States of America 37 32541028
2019 CAR T-cell bioengineering: Single variable domain of heavy chain antibody targeted CARs. Advanced drug delivery reviews 37 31004624
2024 Fueling CARs: metabolic strategies to enhance CAR T-cell therapy. Experimental hematology & oncology 35 38987856
2021 Remote controlling of CAR-T cells and toxicity management: Molecular switches and next generation CARs. Translational oncology 35 33789222
2013 Simultaneous hyperspectral differential-CARS, TPF and SHG microscopy with a single 5 fs Ti:Sa laser. Optics express 35 23546091
2018 Increasing T Cell Versatility with SUPRA CARs. Cell 34 29856949
2015 Seatbelts in CAR therapy: How Safe Are CARS? Pharmaceuticals (Basel, Switzerland) 34 26110321
2020 Rapid and Effective Generation of Nanobody Based CARs using PCR and Gibson Assembly. International journal of molecular sciences 33 32019116
2020 Driving CARs with alternative navigation tools - the potential of engineered binding scaffolds. The FEBS journal 32 32794303
2017 CARs in the Lead Against Multiple Myeloma. Current hematologic malignancy reports 32 28233151
2015 A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs. Blood 32 26065655
2021 CARs and beyond: tailoring macrophage-based cell therapeutics to combat solid malignancies. Journal for immunotherapy of cancer 31 34462325
2017 Driving CARs on the Highway to Solid Cancer: Some Considerations on the Adoptive Therapy with CAR T Cells. Human gene therapy 30 28810803
2014 Hyperspectral and differential CARS microscopy for quantitative chemical imaging in human adipocytes. Biomedical optics express 30 24877002
2010 Genetic variation in innate immunity pathways and their potential contribution to the SIRS/CARS debate: evidence from human studies and animal models. Journal of innate immunity 30 20431282
2022 Targeting glycans for CAR therapy: The advent of sweet CARs. Molecular therapy : the journal of the American Society of Gene Therapy 29 35821636
2020 CARs: Beyond T Cells and T Cell-Derived Signaling Domains. International journal of molecular sciences 29 32429316
2019 Carboxylic acid reductases (CARs): An industrial perspective. Journal of biotechnology 29 31430498
2018 Advances in the use of natural receptor- or ligand-based chimeric antigen receptors (CARs) in haematologic malignancies. Best practice & research. Clinical haematology 29 29909918
2022 Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction. Frontiers in cell and developmental biology 27 36578789
2022 Advances in modular control of CAR-T therapy with adapter-mediated CARs. Advanced drug delivery reviews 25 35618140
2020 Engineering Cytoplasmic Signaling of CD28ζ CARs for Improved Therapeutic Functions. Frontiers in immunology 25 32636832
2019 Paving New Roads for CARs. Trends in cancer 24 31706506
2022 Targeting CD19 for diffuse large B cell lymphoma in the era of CARs: Other modes of transportation. Blood reviews 22 35989138
2022 CARs: a new approach for the treatment of autoimmune diseases. Science China. Life sciences 22 36346550
2020 ADCs, BiTEs, CARs, and Small Molecules: A New Era of Targeted Therapy in Non-Hodgkin Lymphoma. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 22 32421455
2023 Determination of corn protein content using near-infrared spectroscopy combined with A-CARS-PLS. Food chemistry: X 21 37096170
2018 CARs and other T cell therapies for MM: The clinical experience. Best practice & research. Clinical haematology 21 29909915
2022 Multipurposing CARs: Same engine, different vehicles. Molecular therapy : the journal of the American Society of Gene Therapy 20 35151842
2021 Potent, Selective CARs as Potential T-Cell Therapeutics for HPV-positive Cancers. Journal of immunotherapy (Hagerstown, Md. : 1997) 20 34432728
2021 CARS senses cysteine deprivation to activate AMPK for cell survival. The EMBO journal 20 34472622
2020 Harnessing T Cells to Target Pediatric Acute Myeloid Leukemia: CARs, BiTEs, and Beyond. Children (Basel, Switzerland) 20 32079207
2019 Single variable domains from the T cell receptor β chain function as mono- and bifunctional CARs and TCRs. Scientific reports 20 31754147
2020 T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road. Cells 19 32630096
2004 Hybrid cars now, fuel cell cars later. Science (New York, N.Y.) 19 15310893
2024 Inhibitory CARs fail to protect from immediate T cell cytotoxicity. Molecular therapy : the journal of the American Society of Gene Therapy 18 38384128
2018 Engineering therapeutic T cells to suppress alloimmune responses using TCRs, CARs, or BARs. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 18 29603617
2013 Functional analysis of the carS gene of Fusarium fujikuroi. Molecular genetics and genomics : MGG 18 23543145
2022 Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs). International journal of molecular sciences 17 36430728
2019 Comparative transcriptomic analysis unveils interactions between the regulatory CarS protein and light response in Fusarium. BMC genomics 17 30665350
2011 Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. Cancer immunology, immunotherapy : CII 17 22131062
2021 Novel immune engagers and cellular therapies for metastatic castration-resistant prostate cancer: do we take a BiTe or ride BiKEs, TriKEs, and CARs? Prostate cancer and prostatic diseases 16 34035459
2020 Eosinophils and Neutrophils-Molecular Differences Revealed by Spontaneous Raman, CARS and Fluorescence Microscopy. Cells 16 32906767
2016 From therapeutic antibodies to chimeric antigen receptors (CARs): making better CARs based on antigen-binding domain. Expert opinion on biological therapy 16 27618260
2022 Label-Free Live-Cell Imaging of Internalized Microplastics and Cytoplasmic Organelles with Multicolor CARS Microscopy. Environmental science & technology 15 35133146
2024 Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation. Nature metabolism 14 38658805
2021 Anti-CD19 CARs displayed at the surface of lentiviral vector particles promote transduction of target-expressing cells. Molecular therapy. Methods & clinical development 14 33768128
2023 Localization of unlabeled bepirovirsen antisense oligonucleotide in murine tissues using in situ hybridization and CARS imaging. RNA (New York, N.Y.) 13 37460153
2022 Do Treg Speed Up with CARs? Chimeric Antigen Receptor Treg Engineered to Induce Transplant Tolerance. Transplantation 13 36226849
2022 Modern Advances in CARs Therapy and Creating a New Approach to Future Treatment. International journal of molecular sciences 13 36499331
2019 Quantitative Mapping of Triacylglycerol Chain Length and Saturation Using Broadband CARS Microscopy. Biophysical journal 13 31153590
2015 Roadblocks to success for RNA CARs in solid tumors. Oncoimmunology 13 25964863
2015 Fast Cars and No Brakes: Autologous Stem Cell Transplantation as a Platform for Novel Immunotherapies. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 13 26485445
1990 Carbohydrate and hydrophobic-carbohydrate recognition sites (CARS and HY-CARS) in solubilized glycosyltransferases. Indian journal of biochemistry & biophysics 13 2129345
2024 Aptamer-Based Nongenetic Reprogramming of CARs Enables Flexible Modulation of T Cell-Mediated Tumor Immunotherapy. ACS central science 12 38680567

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