CoChat
Sign Up
Cited by 23

The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.

Cold shock domain-containing protein E1 is a posttranscriptional regulator of the LDL receptor

Smith, Geoffrey A., Padmanabhan, Arun, Lau, Bryan H., Pampana, Akhil, Li, Li, Lee, Clara Y., Pelonero, Angelo, Nishino, Tomohiro, Sadagopan, Nandhini, Xia, Vivian Q., Jain, Rajan, Natarajan, Pradeep, Wu, Roland S., Black, Brian L., Srivastava, Deepak, Shokat, Kevan M., Chorba, John S.·2022·Science Translational Medicine
DOI 10.1126/scitranslmed.abj8670PMC PMC10174261

Published version of a preprint

Open this paper in CoChat — free account

Abstract

The low-density lipoprotein receptor (LDLR) controls cellular delivery of cholesterol and clears LDL from the bloodstream, protecting against atherosclerotic heart disease, the leading cause of death in the United States. We therefore sought to identify regulators of the LDLR beyond the targets of current therapies and known causes of familial hypercholesterolemia. We found that cold shock domain–containing protein E1 (CSDE1) enhanced hepatic LDLR messenger RNA (mRNA) decay via its 3′ untranslated region and regulated atherogenic lipoproteins in vivo. Using parallel phenotypic genome-wide CRISPR interference screens in a tissue culture model, we identified 40 specific regulators of the LDLR that were not previously identified by observational human genetic studies. Among these, we demonstrated that, in HepG2 cells, CSDE1 regulated the LDLR at least as strongly as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In addition, we showed that hepatic gene silencing of Csde1 treated diet-induced dyslipidemia in mice to a similar degree as Pcsk9 silencing. These results suggest the therapeutic potential of targeting CSDE1 to manipulate the posttranscriptional regulation of the LDLR mRNA for the prevention of cardiovascular disease. Our approach of modeling a clinically relevant phenotype in a forward genetic screen, followed by mechanistic pharmacologic dissection and in vivo validation, may serve as a generalizable template for the identification of therapeutic targets in other human disease states.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.abj8670

Cites

17 of 17 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • CSDE1, hnRNPD, hnRNPI, KSRP, ZFP36L1, and ZFP36L2 bind to AREs in the 3′UTR and lead to degradation of LDLR mRNA, decreasing LDLR.

    “CSDE1, hnRNPD, hnRNPI, KSRP, ZFP36L1, ZFP36L2 Bind to AREs in the 3′UTR and lead to degradation of LDLR mRNA ↓ [29-31]”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [31]

    The Results section reports that CSDE1 promotes LDLR mRNA decay through its 3′UTR and that an ARE is required for its full effect. The Discussion says CSDE1 was found to bind LDLR 3′UTR transcripts, but the paper does not establish that it binds the ARE itself or substantiate the same mechanism for all six listed proteins. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Individual cells with disrupted PCSK9 will remain sensitive to the extracellular PCSK9 secreted by neighboring cells, precluding their development of a LDLR-mediated phenotype in this study and in prior pooled CRISPR screens.

    “For example, individual cells with disrupted PCSK9 will remain sensitive to the extracellular PCSK9 secreted by neighboring cells, precluding their development of a LDLR-mediated phenotype in this study and in prior pooled CRISPR screens for LDL uptake or LDLR abundance56,80,93.”

    From Functional interrogation of cellular Lp(a) uptake by genome-scale CRISPR screening (2025) · cites this paper as [80]

    The Results sections describe a pooled CRISPRi screen for surface LDLR abundance and state that PCSK9 acts extracellularly in LDLR regulation. They do not say that PCSK9-disrupted cells remained sensitive to PCSK9 from neighboring cells, or that this prevented an LDLR phenotype in this or prior pooled screens. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • LDLR mRNA is regulated via multiple microRNAs, alternative splicing to produce non-functional LDLR protein, and regulation of LDLR mRNA decay.

    “At the post-transcriptional level, LDLR mRNA is regulated via several mechanisms including multiple microRNAs [30], alternative splicing to produce non-functional LDLR protein [31], and regulation of LDLR mRNA decay [32].”

    From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [32]

  • Experimental evidence has recapitulated key modulators of cellular LDL uptake, as well as posttranscriptional and posttranslational regulators of LDLR.

    “Moreover, experimental evidence has recapitulated key modulators of cellular LDL uptake, as well as posttranscriptional and posttranslational regulators of LDLR79–82.”

    From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [80]

  • A whole-genome CRISPR-Cas9 screen identified CSDE1 as an RBP that enhances LDLR mRNA decay, confirmed in HepG2 cells, zebrafish, and mice.

    “More recently, the application of a whole-genome CRISPR-Cas9 screen further identified CSDE1 as another RBP that enhances LDLR mRNA decay, an effect confirmed in various models including HepG2 cells, zebrafish, and mice [31].”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [31]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 91

  1. 10.1126/science.3513311 · DOI · Paper page
  2. K. D. Kochanek, J. Xu, E. Arias, Mortality in the United States, 2019. NCHS Data Brief 395, 1–8 (2020).
  3. 10.1212/WNL.0000000000007853 · DOI
  4. 10.1001/jamacardio.2018.2258 · DOI
  5. 10.1210/jendso/bvz015 · DOI
  6. 10.1038/s41588-018-0222-9 · DOI · Paper page
  7. 10.1016/S0140-6736(12)62127-8 · DOI
  8. 10.1038/s41467-019-12869-0 · DOI
  9. 10.1016/j.cell.2014.09.029 · DOI · Paper page
  10. 10.7554/eLife.19760 · DOI · Paper page
  11. 10.1126/science.6248960 · DOI
  12. 10.1016/S0006-2952(01)00790-0 · DOI
  13. 10.1161/01.ATV.0000046229.77566.E5 · DOI
  14. 10.1161/01.ATV.0000134621.14315.43 · DOI · Paper page
  15. 10.1172/JCI29383 · DOI · Paper page
  16. 10.1016/S0021-9258(17)38120-6 · DOI
  17. 10.1074/jbc.M409699200 · DOI · Paper page
  18. 10.1073/pnas.0501652102 · DOI · Paper page
  19. 10.1073/pnas.0903849106 · DOI · Paper page
  20. 10.1016/j.biocel.2004.02.007 · DOI
  21. 10.1074/jbc.R117.781823 · DOI
  22. 10.1126/science.1168974 · DOI · Paper page
  23. 10.1016/j.celrep.2017.05.009 · DOI
  24. 10.1093/nar/gky1038 · DOI
  25. 10.1038/nature09270 · DOI · Paper page
  26. 10.1038/s41467-018-05747-8 · DOI
  27. 10.1038/ng.3977 · DOI · Paper page
  28. 10.1038/s41586-018-0579-z · DOI · Paper page
  29. 10.1007/978-1-4939-6875-6_5 · DOI
  30. 10.1016/j.bcp.2013.03.021 · DOI
  31. 10.1038/78966 · DOI
  32. 10.3390/genes10010021 · DOI
  33. 10.1016/j.cellsig.2011.08.009 · DOI
  34. 10.1038/ncb1998 · DOI
  35. C. L. Gao, J. G. Zhu, Y. P. Zhao, X. H. Chen, C. B. Ji, C. M. Zhang, C. Zhu, Z. K. Xia, Y. Z. Peng, X. R. Guo, Mitochondrial dysfunction is induced by the overexpression of UCP4 in 3T3-L1 adipocytes. Int. J. Mol. Med. 25, 71–80 (2010).
  36. 10.1074/jbc.M113.508812 · DOI
  37. 10.15252/embj.201899708 · DOI
  38. 10.1038/s41598-017-05768-1 · DOI
  39. 10.1172/JCI77095 · DOI
  40. 10.1172/JCI44213 · DOI
  41. 10.1083/jcb.200305145 · DOI
  42. 10.1073/pnas.92.12.5496 · DOI
  43. 10.1074/jbc.M501029200 · DOI · Paper page
  44. Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).
  45. 10.1371/journal.pbio.2001882 · DOI
  46. 10.1194/jlr.M700437-JLR200 · DOI
  47. 10.1074/jbc.M100432200 · DOI
  48. 10.1074/jbc.M109.052407 · DOI
  49. 10.1186/s12964-019-0496-2 · DOI
  50. 10.1210/me.2005-0333 · DOI
  51. 10.1038/s41598-018-20518-7 · DOI
  52. 10.1101/gad.1219104 · DOI
  53. 10.1016/S0022-2275(20)33870-0 · DOI · Paper page
  54. 10.1194/jlr.M800375-JLR200 · DOI · Paper page
  55. 10.1093/nar/29.1.246 · DOI
  56. 10.1194/jlr.D081521 · DOI
  57. 10.1016/j.devcel.2018.06.003 · DOI
  58. 10.1016/0021-9150(85)90138-8 · DOI
  59. 10.1161/01.ATV.19.8.1938 · DOI
  60. 10.1161/01.ATV.0000201071.49029.17 · DOI
  61. 10.1016/j.cmet.2016.11.001 · DOI
  62. 10.1161/CIRCRESAHA.114.302937 · DOI
  63. 10.1016/S0140-6736(17)32290-0 · DOI · Paper page
  64. 10.1074/jbc.M009423200 · DOI · Paper page
  65. 10.1161/CIRCGEN.120.003029 · DOI · Paper page
  66. 10.1161/ATVBAHA.121.316764 · DOI
  67. 10.1038/s41467-017-01744-5 · DOI
  68. 10.1128/JVI.77.6.3353-3359.2003 · DOI
  69. 10.4161/rna.2.3.2203 · DOI
  70. 10.1016/j.molcel.2009.09.042 · DOI
  71. 10.1126/sciadv.aax2166 · DOI
  72. 10.1016/j.ccell.2016.10.004 · DOI
  73. 10.1126/scitranslmed.abe9117 · DOI
  74. 10.1038/s41586-021-03534-y · DOI · Paper page
  75. 10.1002/anie.201708744 · DOI
  76. 10.1056/NEJMoa1409077 · DOI · Paper page
  77. 10.1371/journal.pmed.1001779 · DOI · Paper page
  78. 10.1038/ng.3190 · DOI · Paper page
  79. J. M. Baker, F. M. Boyce, High-throughput functional screening using a homemade dual-glow luciferase assay. J. Vis. Exp. 88, e50282 (2014).
  80. 10.1074/jbc.RA117.000754 · DOI · Paper page
  81. J. S. Chorba, A. M. Galvan, K. M. Shokat, A high-throughput luciferase assay to evaluate proteolysis of the single-turnover protease PCSK9. J. Vis. Exp. 138, e58265 (2018).
  82. 10.1186/s13059-014-0550-8 · DOI · Paper page
  83. 10.1093/bioinformatics/btp616 · DOI · Paper page
  84. 10.1007/978-1-4939-3578-9_19 · DOI
  85. 10.1093/nar/gkw377 · DOI · Paper page
  86. 10.1093/bioinformatics/btw313 · DOI
  87. 10.1002/1097-0320(20010901)45:1<47::AID-CYTO1143>3.0.CO;2-A · DOI
  88. 10.1038/nmeth.1318 · DOI
  89. 10.1371/journal.pone.0018556 · DOI
  90. 10.1038/nmeth.1515 · DOI
  91. 10.1093/nar/gky1049 · DOI · Paper page

Cited by

Sorted by citations

Metadata

Authors
Smith, G. A., Padmanabhan, A., Lau, B. H., Pampana, A., Li, L., Lee, C. Y., Pelonero, A., Nishino, T., Sadagopan, N., Xia, V. Q., Jain, R., Natarajan, P., Wu, R. S., Black, B. L., Srivastava, D., Shokat, K. M., & Chorba, J. S.
Affiliations
  • Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Division of Cardiology, UCSF Health, San Francisco, CA 94143, USA.
  • Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Department of Medicine and Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
  • Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-09-14
Volume
14
Issue
662
ISSN
  • 1946-6234
  • 1946-6242
DOI
10.1126/scitranslmed.abj8670
PMC
PMC10174261
Cited by
23
References
17
Language
en

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review