Article | Published:

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

Oncogenevolume 37pages34153425 (2018) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 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.

  2. 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.

  3. 3.

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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 11.

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

  12. 12.

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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 24.

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

  25. 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.

  26. 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.

  27. 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.

  28. 28.

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

  29. 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.

  30. 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.

  31. 31.

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

  32. 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.

  33. 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.

  34. 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.

  35. 35.

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

  36. 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.

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

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

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. Search for You-Take Oh in:

  2. Search for Guoqing Qian in:

  3. Search for Jiusheng Deng in:

  4. Search for Shi-Yong Sun in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Shi-Yong Sun.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

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