1. Academic Validation
  2. The protein kinase D1-mediated classical protein secretory pathway regulates the Ras oncogene-induced senescence response

The protein kinase D1-mediated classical protein secretory pathway regulates the Ras oncogene-induced senescence response

  • J Cell Sci. 2018 Mar 16;131(6):jcs207217. doi: 10.1242/jcs.207217.
Yuanyuan Su 1 Pengfeng Wang 1 Hong Shen 1 Zhaomeng Sun 1 Chenzhong Xu 1 Guodong Li 1 Tanjun Tong 1 Jun Chen 2
Affiliations

Affiliations

  • 1 Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
  • 2 Peking University Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China cjbiochem@bjmu.edu.cn.
Abstract

Senescent cells develop a senescence-associated secretory phenotype (SASP). The factors secreted by cells with a SASP have multiple biological functions that are mediated in an autocrine or paracrine manner. However, the status of the protein kinase D1 (PKD1; also known as PRKD1)-mediated classical protein secretory pathway, from the trans-Golgi network (TGN) to the cell surface, during cellular senescence and its role in the cellular senescence response remain unknown. Here, we show that the activities or quantities of critical components of this pathway, including PKD1, ADP-ribosylation factor 1 (ARF1) and phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), at the TGN are increased in senescent cells. Blocking of this pathway decreases IL-6 and IL-8 (hereafter IL-6/IL-8) secretion and results in IL-6/IL-8 accumulation in SASP-competent senescent cells. Inhibition of this pathway reduces IL-6/IL-8 secretion during Ras oncogene-induced senescence (OIS), retards Ras OIS and alleviates its associated ER stress and Autophagy. Finally, targeting of this pathway triggers cell death in SASP factor-producing senescent cells due to the intracellular accumulation of massive amounts of IL-6/IL-8. Taken together, our results unveil the hyperactive state of the protein secretory pathway in SASP-competent senescent cells and its critical functions in mediating SASP factor secretion and the Ras OIS process, as well as in determining the fate of senescent cells.

Keywords

Classical protein secretory pathway; IL-6; Oncogene-induced senescence; Protein kinase D1; Senescence-associated secretory phenotype; Trans-Golgi network.

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