Protein kinase D1-mediated classical protein secretory pathway regulates oncogene Ras-induced senescent response.

5 years ago

Protein kinase D1-mediated classical protein secretory pathway regulates oncogene Ras-induced senescent response.

Pengfeng Wang, Jun Chen, Zhaomeng Sun, Tanjun Tong, Yuanyuan Su, Hong Shen, Chenzhong Xu, Guodong Li

Senescent cells develop senescence-associated secretory phenotype (SASP) which possesses multiple biological functions via autocrine or paracrine manner. However, the status of the protein kinase D1 (PKD1)-mediated classical protein secretory pathway from trans-Golgi network (TGN) to cell surface during cellular senescence and its role in cellular senescent response remain unknown. Here, we show that the activities or quantities of the critical components of this pathway including PKD1, ADP-ribosylation factor 1 (ARF1), and phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) at TGN are increased in senescent cells. Block of this pathway decreases IL-6/IL-8 secretion and results in IL-6/IL-8 accumulation in SASP-competent senescent cells. Intervention of this pathway reduces IL-6/IL-8 secretion during Ras OIS, retards Ras OIS and alleviates its associated ER stress and autophagy. Last, targeting of this pathway triggers SASP-producing senescent cells death due to the intracellular accumulation of massive IL-6/IL-8. Together, our results unveil the hyperactivity state of protein secretory pathway in SASP-competent senescent cells and its critical functions in mediating SASP factors secretion and Ras OIS process, as well as in determining senescent cells fate.

Publisher URL: http://doi.org/10.1242/jcs.207217

DOI: 10.1242/jcs.207217