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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


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.

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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.

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  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


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The authors declare that they have no conflict of interest.

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Correspondence to Shi-Yong Sun.

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