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:

Monocyte chemotactic protein-induced protein-1 enhances DR5 degradation and negatively regulates DR5 activation-induced apoptosis through its deubiquitinase function

Oncogene volume 37, pages 3415–3425 (2018)Cite this article

Subjects

Abstract

Monocyte chemotactic protein-induced protein-1 (MCPIP1; also called Regnase-1) encoded by the ZC3H12A gene critically regulates inflammatory responses and immune homeostasis primarily by RNase-dependent and -independent mechanisms. However, the relationship of MCPIP1 with apoptosis and cancer and the underlying mechanisms are largely unclear. The current study has demonstrated a previously uncovered connection between MCPIP1 and the negative regulation of death receptor 5 (DR5; also known as TRAIL-R2 or killer/DR5), a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is produced endogenously by various immune cells such as T cells. Our findings have revealed that MCPIP1 decreases both total cellular and cell surface DR5, primarily through modulating DUB-mediated protein autophagic/lysosomal degradation. Suppression of MCPIP1 by gene knockdown induces the formation of death-induced signaling complex (DISC) and enhances TRAIL or DR5 activation-induced apoptosis in cancer cells. Moreover, we demonstrated an inverse correlation between MCPIP1 expression and DR5 expression/cell sensitivity to DR5 activation-induced apoptosis in cancer cells. Our findings warrant future investigation of the roles of negative regulation of DR5 by MCPIP1 in cancer and in T-cell immunity.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Zhou L, Azfer A, Niu J, Graham S, Choudhury M, Adamski FM, et al. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res. 2006;98:1177–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jura J, Skalniak L, Koj A. Monocyte chemotactic protein-1-induced protein-1 (MCPIP1) is a novel multifunctional modulator of inflammatory reactions. Biochim Biophys Acta. 2012;1823:1905–13.

    Article  CAS  PubMed  Google Scholar 

  3. Xu J, Fu S, Peng W, Rao Z. MCP-1-induced protein-1, an immune regulator. Protein Cell. 2012;3:903–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K, et al. Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell. 2013;153:1036–49.

    Article  CAS  PubMed  Google Scholar 

  5. Matsushita K, Takeuchi O, Standley DM, Kumagai Y, Kawagoe T, Miyake T, et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature. 2009;458:1185–90.

    Article  CAS  PubMed  Google Scholar 

  6. Liang J, Saad Y, Lei T, Wang J, Qi D, Yang Q, et al. MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-kappaB signaling. J Exp Med. 2010;207:2959–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Suzuki HI, Arase M, Matsuyama H, Choi YL, Ueno T, Mano H, et al. MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. Mol Cell. 2011;44:424–36.

    Article  CAS  PubMed  Google Scholar 

  8. Lu W, Ning H, Gu L, Peng H, Wang Q, Hou R, et al. MCPIP1 selectively destabilizes transcripts associated with an antiapoptotic gene expression Program in breast cancer cells that can elicit complete tumor regression. Cancer Res. 2016;76:1429–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Skalniak A, Boratyn E, Tyrkalska SD, Horwacik I, Durbas M, Lastowska M, et al. Expression of the monocyte chemotactic protein-1-induced protein 1 decreases human neuroblastoma cell survival. Oncol Rep. 2014;31:2385–92.

    Article  CAS  PubMed  Google Scholar 

  10. Qi D, Huang S, Miao R, She ZG, Quinn T, Chang Y, et al. Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress. J Biol Chem. 2011;286:41692–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Falschlehner C, Schaefer U, Walczak H. Following TRAIL’s path in the immune system. Immunology. 2009;127:145–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gonzalvez F, Ashkenazi A. New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene. 2010;29:4752–65.

    Article  CAS  PubMed  Google Scholar 

  13. Lim B, Allen JE, Prabhu VV, Talekar MK, Finnberg NK, El-Deiry WS. Targeting TRAIL in the treatment of cancer: new developments. Expert Opin Ther Targets. 2015;19:1171–85.

    Article  CAS  PubMed  Google Scholar 

  14. Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H. Nature’s TRAIL—on a path to cancer immunotherapy. Immunity. 2003;18:1–6.

    Article  CAS  PubMed  Google Scholar 

  15. Bellail AC, Qi L, Mulligan P, Chhabra V, Hao C. TRAIL agonists on clinical trials for cancer therapy: the promises and the challenges. Rev Recent Clin Trials. 2009;4:34–41.

    Article  CAS  PubMed  Google Scholar 

  16. Falschlehner C, Ganten TM, Koschny R, Schaefer U, Walczak H. TRAIL and other TRAIL receptor agonists as novel cancer therapeutics. Adv Exp Med Biol. 2009;647:195–206.

    Article  CAS  PubMed  Google Scholar 

  17. Yang A, Wilson NS, Ashkenazi A. Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Curr Opin Cell Biol. 2010;22:837–44.

    Article  CAS  PubMed  Google Scholar 

  18. Twomey JD, Kim SR, Zhao L, Bozza WP, Zhang B. Spatial dynamics of TRAIL death receptors in cancer cells. Drug Resist Update. 2015;19:13–21.

    Article  Google Scholar 

  19. Akazawa Y, Mott JL, Bronk SF, Werneburg NW, Kahraman A, Guicciardi ME, et al. Death receptor 5 internalization is required for lysosomal permeabilization by TRAIL in malignant liver cell lines. Gastroenterology. 2009;136:2365–76. e2361-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Song JJ, Szczepanski MJ, Kim SY, Kim JH, An JY, Kwon YT, et al. c-Cbl-mediated degradation of TRAIL receptors is responsible for the development of the early phase of TRAIL resistance. Cell Signal. 2010;22:553–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang Y, Yoshida T, Zhang B. TRAIL induces endocytosis of its death receptors in MDA-MB-231 breast cancer cells. Cancer Biol Ther. 2009;8:917–22.

    Article  CAS  PubMed  Google Scholar 

  22. Austin CD, Lawrence DA, Peden AA, Varfolomeev EE, Totpal K, De Maziere AM, et al. Death-receptor activation halts clathrin-dependent endocytosis. Proc Natl Acad Sci USA. 2006;103:10283–8.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang Y, Zhang B. TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. Mol Cancer Res. 2008;6:1861–71.

    Article  CAS  PubMed  Google Scholar 

  24. Kolattukudy PE, Niu J. Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway. Circ Res. 2012;110:174–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang K, Niu J, Kim H, Kolattukudy PE. Osteoclast precursor differentiation by MCPIP via oxidative stress, endoplasmic reticulum stress, and autophagy. J Mol Cell Biol. 2011;3:360–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Younce CW, Kolattukudy PE. MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. Biochem J. 2010;426:43–53.

    Article  CAS  PubMed  Google Scholar 

  27. Liu H, Fang S, Wang W, Cheng Y, Zhang Y, Liao H, et al. Macrophage-derived MCPIP1 mediates silica-induced pulmonary fibrosis via autophagy. Part Fibre Toxicol. 2016;13:55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 2011;8:528–39.

    Article  CAS  PubMed  Google Scholar 

  29. Oh YT, Yue P, Zhou W, Balko JM, Black EP, Owonikoko TK, et al. Oncogenic Ras and B-Raf proteins positively regulate death receptor 5 expression through co-activation of ERK and JNK signaling. J Biol Chem. 2012;287:257–67.

    Article  CAS  PubMed  Google Scholar 

  30. Anel A, Bosque A, Naval J, Pineiro A, Larrad L, Alava MA, et al. Apo2L/TRAIL and immune regulation. Front Biosci. 2007;12:2074–84.

    Article  CAS  PubMed  Google Scholar 

  31. Shanker A, Sayers T. Sensitizing tumor cells to immune-mediated cytotoxicity. Adv Exp Med Biol. 2007;601:163–71.

    Article  PubMed  Google Scholar 

  32. Shin GC, Kang HS, Lee AR, Kim KH. Hepatitis B virus-triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response. Autophagy. 2016;12:2451–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Di X, Zhang G, Zhang Y, Takeda K, Rivera Rosado LA, Zhang B. Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5. Oncotarget. 2013;4:1349–64.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Chen L, Meng Y, Sun Q, Zhang Z, Guo X, Sheng X, et al. Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation. Cell Death Dis. 2016;7:e2334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mellman I, Yarden Y. Endocytosis and cancer. Cold Spring Harb Perspect Biol. 2013;5:a016949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Oh YT, Deng L, Deng J, Sun SY. The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5. Sci Rep. 2017;7:8027.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Yao W, Yue P, Zhang G, Owonikoko TK, Khuri FR, Sun SY. Enhancing therapeutic efficacy of the MEK inhibitor, MEK162, by blocking autophagy or inhibiting PI3K/Akt signaling in human lung cancer cells. Cancer Lett. 2015;364:70–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Oh YT, Liu X, Yue P, Kang S, Chen J, Taunton J, et al. ERK/ribosomal S6 kinase (RSK) signaling positively regulates death receptor 5 expression through co-activation of CHOP and Elk1. J Biol Chem. 2010;285:41310–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fu L, Lin YD, Elrod HA, Yue P, Oh Y, Li B, et al. c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL. Mol Cancer. 2010;9:315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dhandapani L, Yue P, Ramalingam SS, Khuri FR, Sun SY. Retinoic acid enhances TRAIL-induced apoptosis in cancer cells by upregulating TRAIL receptor 1 expression. Cancer Res. 2011;71:5245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sun SY, Liu X, Zou W, Yue P, Marcus AI, Khuri FR. The farnesyltransferase inhibitor lonafarnib induces CCAAT/enhancer-binding protein homologous protein-dependent expression of death receptor 5, leading to induction of apoptosis in human cancer cells. J Biol Chem. 2007;282:18800–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are thankful to Drs. M. Fu and J. Liu for generously providing us with MCPIP1 expression plasmids and MCPIP1-inducible cell line. We are also grateful to Dr. A. Hammond for editing the manuscript. This study was supported by Halpern Research Scholar award (to S-YS). S-YS is a Georgia Research Alliance Distinguished Cancer Scientist and Halpern Research Scholar.

Author information

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    You-Take Oh, Guoqing Qian, Jiusheng Deng & Shi-Yong Sun

Authors
  1. You-Take Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guoqing Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiusheng Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shi-Yong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shi-Yong Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oh, YT., Qian, G., Deng, J. et al. Monocyte chemotactic protein-induced protein-1 enhances DR5 degradation and negatively regulates DR5 activation-induced apoptosis through its deubiquitinase function. Oncogene 37, 3415–3425 (2018). https://doi.org/10.1038/s41388-018-0200-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0200-9

This article is cited by

Search

Advanced search

Quick links