Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression

Oncogene volume 44, pages 694–708 (2025)Cite this article

Subjects

Abstract

Multiple myeloma (MM), the world’s second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo. Mechanistically, TRIB3 directly interacts with structure-specific recognition protein 1 (SSRP1) and ubiquitin-specific peptidase 10 (USP10), facilitating the formation of a TRIB3/USP10/SSRP1 ternary complex. This complex stabilizes SSRP1 via USP10-mediated deubiquitination, thereby driving MM cell proliferation. Furthermore, a stapled peptide, SP-A, was developed, which effectively disrupts the TRIB3/USP10/SSRP1 complex, leading to a decrease in SSRP1 levels by inhibiting its stabilization through USP10. Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib. Given the critical role of the TRIB3/USP10/SSRP1 complex in MM pathophysiology, it represents a promising therapeutic target for MM treatment.

In MM cells, TRIB3, USP10 and SSRP1 form a ternary complex and TRIB3 enhances the deubiquitinating effect of USP10 on SSRP1, leading to malignant progression of MM. In the case of drug intervention, SP-A attenuates the binding of SSRP1 and USP10 by inhibiting protein interactions between TRIB3 and SSRP1 and promoted SSRP1 protein degradation, leading to significant inhibition of MM development. Visual abstract created with Biorender.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Clinical significance of pseudokinase TRIB3 in multiple myeloma (MM).
Fig. 2: TRIB3 promotes MM development in vitro and in vivo.
Fig. 3: TRIB3 directly interact with SSRP1.
Fig. 4: TRIB3 regulates SSRP1 protein degradation via the ubiquitin-proteasome pathway.
Fig. 5: TRIB3, USP10 and SSRP1 form a ternary complex.
Fig. 6: TRIB3 enhances the deubiquitinating effect of USP10 on SSRP1.
Fig. 7: Stapled peptide disrupts TRIB3/USP10/SSRP1 complex to inhibit MM development.
Fig. 8: Stapled peptide sensitizes BTZ treatment in multiple myeloma.

Similar content being viewed by others

Data availability

All data and materials are available upon request by contacting the corresponding author.

References

  1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046–60.

    Article  CAS  PubMed  Google Scholar 

  2. Van de Donk NWCJ, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397:410–27.

    Article  PubMed  Google Scholar 

  3. Shen YJ, Mishima Y, Shi J, Sklavenitis-Pistofidis R, Redd RA, Moschetta M, et al. Progression signature underlies clonal evolution and dissemination of multiple myeloma. Blood. 2021;137:2360–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395:132–41.

    Article  CAS  PubMed  Google Scholar 

  5. Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390:301–13.

    Article  CAS  PubMed  Google Scholar 

  6. Moreau P, Garfall AL, van de Donk NWCJ, Nahi H, San-Miguel JF, Oriol A, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387:495–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Minnie SA, Hill GR. Immunotherapy of multiple myeloma. J Clin Invest. 2020;130:1565–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Attwood MM, Fabbro D, Sokolov AV, Knapp S, Schiöth HB. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov. 2021;20:839–61.

    Article  CAS  PubMed  Google Scholar 

  9. Roskoski RJ. Properties of FDA-approved small molecule protein kinase inhibitors: a 2023 update. Pharmacol Res. 2023;187:106552.

    Article  CAS  PubMed  Google Scholar 

  10. Kung JE, Jura N. Prospects for pharmacological targeting of pseudokinases. Nat Rev Drug Discov. 2019;18:501–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Haikala HM, Lopez T, Köhler J, Eser PO, Xu M, Zeng Q, et al. EGFR inhibition enhances the cellular uptake and antitumor-activity of the HER3 antibody-drug conjugate HER3-DXd. Cancer Res. 2022;82:130–41.

    Article  CAS  PubMed  Google Scholar 

  12. Yang X, Cruz MI, Nguyen EV, Huang C, Schittenhelm RB, Luu J, et al. The pseudokinase NRBP1 activates Rac1/Cdc42 via P-Rex1 to drive oncogenic signalling in triple-negative breast cancer. Oncogene. 2023;42:833–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tabrizian N, Nouruzi S, Cui CJ, Kobelev M, Namekawa T, Lodhia I, et al. ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer. Cell Rep. 2023;42:112937.

    Article  CAS  PubMed  Google Scholar 

  14. Arif A, Alameri AA, Tariq UB, Ansari SA, Sakr HI, Qasim MT, et al. The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer. Int Immunopharmacol. 2023;114:109581.

    Article  CAS  PubMed  Google Scholar 

  15. Yu JM, Sun W, Wang ZH, Liang X, Hua F, Li K, et al. TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription. Nat Commun. 2019;10:5720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shang S, Yang YW, Chen F, Yu L, Shen SH, Li K, et al. TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer. Sci Transl Med. 2022;14:eabf0992.

    Article  CAS  PubMed  Google Scholar 

  17. Hua F, Li K, Yu JJ, Lv XX, Yan J, Zhang XW, et al. TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations. Nat Commun. 2015;6:7951.

    Article  CAS  PubMed  Google Scholar 

  18. Ehteda A, Simon S, Franshaw L, Giorgi FM, Liu J, Joshi S, et al. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG. Cell Rep. 2021;35:108994.

    Article  CAS  PubMed  Google Scholar 

  19. Falbo L, Raspelli E, Romeo F, Fiorani S, Pezzimenti F, Casagrande F, et al. SSRP1-mediated histone H1 eviction promotes replication origin assembly and accelerated development. Nat Commun. 2020;11:1345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mo J, Liu F, Sun X, Huang H, Tan K, Zhao X, et al. Inhibition of the FACT complex targets aberrant hedgehog signaling and overcomes resistance to smoothened antagonists. Cancer Res. 2021;81:3105–20.

    Article  CAS  PubMed  Google Scholar 

  21. Gao Y, Li C, Wei L, Teng Y, Nakajima S, Chen X, et al. SSRP1 cooperates with PARP and XRCC1 to facilitate single-strand dna break repair by chromatin priming. Cancer Res. 2017;77:2674–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hossan T, Nagarajan S, Baumgart SJ, Xie W, Magallanes RT, Hernandez C, et al. Histone chaperone SSRP1 is essential for wnt signaling pathway activity during osteoblast differentiation. Stem Cells. 2016;34:1369–76.

    Article  CAS  PubMed  Google Scholar 

  23. Mo J, Tan K, Dong Y, Lu W, Liu F, Mei Y, et al. Therapeutic targeting the oncogenic driver EWSR1:FLI1 in Ewing sarcoma through inhibition of the FACT complex. Oncogene. 2023;42:11–25.

    Article  CAS  PubMed  Google Scholar 

  24. Martens S, Bridelance J, Roelandt R, Vandenabeele P, Takahashi N. MLKL in cancer: more than a necroptosis regulator. Cell Death Differ. 2021;28:1757–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhan F, Barlogie B, Arzoumanian V, Huang Y, Williams DR, Hollmig K, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood. 2007;109:1692–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fetisov TI, Borunova AA, Antipova AS, Antoshina EE, Trukhanova LS, Gorkova TG, et al. Targeting features of curaxin CBL0137 on hematological malignancies in vitro and in vivo. Biomedicines. 2023;11:230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ohtake F, Saeki Y, Ishido S, Kanno J, Tanaka K. The K48-K63 branched ubiquitin chain regulates NF-κB signaling. Mol Cell. 2016;64:251–66.

    Article  CAS  PubMed  Google Scholar 

  28. Chen Q, Zheng W, Guan J, Liu H, Dan Y, Zhu L, et al. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death Differ. 2023;30:137–51.

    Article  CAS  PubMed  Google Scholar 

  29. Brisuda A, Ho JCS, Kandiyal PS, Ng JT, Ambite I, Butler DSC, et al. Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex. Nat Commun. 2021;12:3427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Park IS, Kim S, Yim Y, Park G, Choi J, Won C, et al. Multifunctional synthetic nano-chaperone for peptide folding and intracellular delivery. Nat Commun. 2022;13:4568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lai Y, Fois G, Flores JR, Tuvim MJ, Zhou Q, Yang K, et al. Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides. Nature. 2022;603:949–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang X, Shan G, Li N, Chen J, Ji C, Li X, et al. An autophagy-inducing stapled peptide induces mitochondria dysfunction and triggers autotic cell death in triple-negative breast cancer. Cell Death Discov. 2023;9:303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hawley KY, Eclov RJ, Schnorenberg MR, Tian Y, Shah RN, Thomas-Toth AT, et al. Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function. Proc Natl Acad Sci USA. 2022;119:e2209044119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adapter NPL4. Nature. 2017;552:194–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ross NT, Lohmann F, Carbonneau S, Fazal A, Weihofen WA, Gleim S, et al. CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing’s sarcoma. Nat Chem Biol. 2020;16:50–59.

    Article  CAS  PubMed  Google Scholar 

  36. Dziekan JM, Yu H, Chen D, Dai L, Wirjanata G, Larsson A, et al. Identifying purine nucleoside phosphorylase as the target of quinine using cellular thermal shift assay. Sci Transl Med. 2019;11:eaau3174.

    Article  CAS  PubMed  Google Scholar 

  37. Martinez Molina D, Jafari R, Ignatushchenko M, Seki T, Larsson EA, Dan C, et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science. 2013;341:84–7.

    Article  PubMed  Google Scholar 

  38. Haertle L, Barrio S, Munawar U, Han S, Zhou X, Simicek M, et al. SinGle-nucleotide Variants And Epimutations Induce Proteasome Inhibitor Resistance In Multiple Myeloma. Clin Cancer Res. 2023;29:279–88.

    Article  CAS  PubMed  Google Scholar 

  39. Cohen YC, Zada M, Wang SY, Bornstein C, David E, Moshe A, et al. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing. Nat Med. 2021;27:491–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Roy M, Liang L, Xiao X, Peng Y, Luo Y, Zhou W, et al. Lycorine downregulates HMGB1 to inhibit autophagy and enhances bortezomib activity in multiple myeloma. Theranostics. 2016;6:2209–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang H, Xiao X, Li Z, Luo S, Hu L, Yi H, et al. Polyphyllin VII, a novel moesin inhibitor, suppresses cell growth and overcomes bortezomib resistance in multiple myeloma. Cancer Lett. 2022;537:215647.

    Article  CAS  PubMed  Google Scholar 

  42. Yu JJ, Zhou DD, Yang XX, Cui B, Tan FW, Wang J, et al. TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target. Nat Commun. 2020;11:3660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li K, Wang F, Yang ZN, Zhang TT, Yuan YF, Zhao CX, et al. TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation. Nat Commun. 2020;11:6316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li K, Wang F, Cao WB, Lv XX, Hua F, Cui B, et al. TRIB3 promotes APL progression through stabilization of the oncoprotein PML-RARα and inhibition of p53-mediated senescence. Cancer Cell. 2017;31:697–710.

    Article  CAS  PubMed  Google Scholar 

  45. Hua F, Shang S, Yang YW, Zhang HZ, Xu TL, Yu JJ, et al. TRIB3 interacts With β-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis. Gastroenterology. 2019;156:708–21.

    Article  CAS  PubMed  Google Scholar 

  46. Liu Y, Zhou K, Zhang N, Wei H, Tan YZ, Zhang Z, et al. FACT caught in the act of manipulating the nucleosome. Nature. 2020;577:426–31.

    Article  CAS  PubMed  Google Scholar 

  47. Hondele M, Stuwe T, Hassler M, Halbach F, Bowman A, Zhang ET, et al. Structural basis of histone H2A-H2B recognition by the essential chaperone FACT. Nature. 2013;499:111–4.

    Article  CAS  PubMed  Google Scholar 

  48. Draetta GF, Depinho RA. Cancer drug discovery faces the FACT. Sci Transl Med. 2011;3:95ps34.

    Article  CAS  PubMed  Google Scholar 

  49. Yuan J, Luo K, Zhang L, Cheville JC, Lou Z. USP10 regulates p53 localization and stability by deubiquitinating p53. Cell. 2010;140:384–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kedersha N, Panas MD, Achorn CA, Lyons S, Tisdale S, Hickman T, et al. G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits. J Cell Biol. 2016;212:845–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lim R, Sugino T, Nolte H, Andrade J, Zimmermann B, Shi C, et al. Deubiquitinase USP10 regulates Notch signaling in the endothelium. Science. 2019;364:188–93.

    Article  CAS  PubMed  Google Scholar 

  52. Sun Y, Cao L, Sheng X, Chen J, Zhou Y, Yang C, et al. WDR79 promotes the proliferation of non-small cell lung cancer cells via USP7-mediated regulation of the Mdm2-p53 pathway. Cell Death Dis. 2017;8:e2743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhu H, Zhang T, Wang F, Yang J, Ding J. Structural insights into the activation of USP46 by WDR48 and WDR20. Cell Discov. 2019;5:34.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Dahlberg CL, Juo P. The WD40-repeat proteins WDR-20 and WDR-48 bind and activate the deubiquitinating enzyme USP-46 to promote the abundance of the glutamate receptor GLR-1 in the ventral nerve cord of Caenorhabditis elegans. J Biol Chem. 2014;289:3444–56.

    Article  CAS  PubMed  Google Scholar 

  55. Lu L, Zhang H, Zhou Y, Lin J, Gao W, Yang T, et al. Polymer chimera of stapled oncolytic peptide coupled with anti-PD-L1 peptide boosts immunotherapy of colorectal cancer. Theranostics. 2022;12:3456–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wu Y, Zhou L, Zou Y, Zhang Y, Zhang M, Xu L, et al. Disrupting the phase separation of KAT8–IRF1 diminishes PD-L1 expression and promotes antitumor immunity. Nat Cancer. 2023;4:382–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tang J, Qu LK, Zhang J, Wang W, Michaelson JS, Degenhardt YY, et al. Critical role for Daxx in regulating Mdm2. Nat Cell Biol. 2006;8:855–62.

    Article  CAS  PubMed  Google Scholar 

  58. Wang Z, Wang P, Zhang J, Gong H, Zhang X, Song J, et al. The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis. Nucleic Acids Res. 2023;51:4774–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are thankful to Dr. Hong Liu from the Xiangya Hospital for supplying the USP10-overexpressing plasmid.

Funding

This study was supported by grants from the National Natural Science Foundation of China (92253201, 32350026, 22334005, 81920108004, 82270127, 81970195, 82370128, and 82100137), the National Key Research and Development Program of China (2021YFA0909400 and 2018YFA0107800), the Natural Science Foundation of Hunan Province (2024JJ3037, 2022JJ30183, 2024JK2112 and 2024JJ4075).

Author information

Author notes

  1. These authors contributed equally: Haiqin Wang, Long Liang.

Authors and Affiliations

  1. Department of Hematology, the Second Xiangya Hospital; School of Life Sciences; Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, 410011, China

    Haiqin Wang, Long Liang, Yifang Xie, Han Gong, Feifan Fan, Chengcai Wen, Yu Jiang, Shiying Lei, Xili Qiu, Hongling Peng, Xiaojuan Xiao & Jing Liu

  2. Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, 410082, China

    Mao Ye

Authors
  1. Haiqin Wang
    View author publications

    Search author on:PubMed Google Scholar

  2. Long Liang
    View author publications

    Search author on:PubMed Google Scholar

  3. Yifang Xie
    View author publications

    Search author on:PubMed Google Scholar

  4. Han Gong
    View author publications

    Search author on:PubMed Google Scholar

  5. Feifan Fan
    View author publications

    Search author on:PubMed Google Scholar

  6. Chengcai Wen
    View author publications

    Search author on:PubMed Google Scholar

  7. Yu Jiang
    View author publications

    Search author on:PubMed Google Scholar

  8. Shiying Lei
    View author publications

    Search author on:PubMed Google Scholar

  9. Xili Qiu
    View author publications

    Search author on:PubMed Google Scholar

  10. Hongling Peng
    View author publications

    Search author on:PubMed Google Scholar

  11. Mao Ye
    View author publications

    Search author on:PubMed Google Scholar

  12. Xiaojuan Xiao
    View author publications

    Search author on:PubMed Google Scholar

  13. Jing Liu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

HW, LL, HP, MY, XX and JL conceived the study. HW wrote the draft of the paper. HW, LL, HP, MY, XX and JL revised the paper for important intellectual content. HG designed, implemented, analyzed and interpreted bioinformatic data. HW, YX, FF, CW, YJ, SL and XQ performed and analyzed the experiments. HP, MY, XX and JL supervised the whole work. All authors read and agreed with the manuscript.

Corresponding authors

Correspondence to Hongling Peng, Mao Ye, Xiaojuan Xiao or Jing Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All the samples of human MM patients used in the study were approved as ethical standards by the Ethics Committee of School of Life Sciences of Central South University and processed in accordance with approved procedure of the committee (approval No. 2022-1-42). Written informed consents were obtained from all patients prior to analysis. All in vivo experiments were approved by the Ethics Committee of School of life sciences of Central South University.

Consent for publication

All co-authors have given their consent to the submitted version of the manuscript for publication.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, H., Liang, L., Xie, Y. et al. Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression. Oncogene 44, 694–708 (2025). https://doi.org/10.1038/s41388-024-03245-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-024-03245-4

This article is cited by

Search

Advanced search

Quick links