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

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.

The Great Escape: how phosphatidylinositol 4-kinases and PI4P promote vesicle exit from the Golgi (and drive cancer)

“…In some tumours the changes to Golgi trafficking, signalling and morphology (28)(29)(30)(31)(32)(33)(34)(35) can be so pronounced that the term "onco-Golgi" has been proposed to capture its altered status in malignant disease (36). Relevant to this concept, gene mutations that lead to increased expression of Golgi-targeted PI4P binding proteins or PI 4-kinases can be associated with a distended Golgi morphology (37) and the anterograde trafficking of proteins (38)(39)(40)(41) that drive angiogenesis (42,43), tumour invasion (44)(45)(46)(47) and metastasis (48)(49)(50)(51).…”

Flavonoids: Broad Spectrum Agents on Chronic Inflammation

“…Flavonoids such as baicalin and kaempferol inhibited the production of some cytokines through NF-κB signaling in aged rat (Kim et al ., 2010; Lim et al ., 2012). Signaling molecules such as protein kinase D1, p38 MAPK, MAPK-activated protein kinase-2 (MK2), and mixed-lineage leukemia 1 (MLL1) have been suggested to play essential roles in producing SASP molecules (Alimbetov et al ., 2016; Capell et al ., 2016; Su et al ., 2018). Besides, several reports have demonstrated the regulation of SASP factors by some microRNAs (Panda et al ., 2017).…”

Protein kinase D1 phosphorylates CBX8 to facilitate the disassociation of PRC1 complex from p16 promoter and promotes cell senescence

“…activates both NF-κB and classical protein secretory pathway to modulate SASP factors expression and secretion thereby promoting cellular senescence (Su et al, 2018;Wang et al, 2014). Therefore, all of these findings suggest that PKD1 promotes cellular senescence via multiple mechanisms.…”

“…As ectopic expression of CBX8 is known to bypass cell senescence by directly suppressing the INK4a/ARF locus (Dietrich et al, 2007), and we previously also reveal that PKD1 promotes Ras OIS (Su et al, 2018;Wang et al, 2014), we then investigated whether PKD1 could phosphorylate CBX8 at S256/311 in Ras OIS and the biological importance of CBX8 S256/311 phosphorylation in cell senescence. To this end, we used IMR90 cells ectopically expressing oncogene Ras protein as a Ras OIS model, and the human lung fibroblast 2BS cells as a replicative senescence model.…”

“…Particularly, PKD1 can phosphorylate class IIa histone deacetylases (HDACs) HDAC5 and HDAC7 in the nucleus, leading them nuclear export, thereby releasing HDAC5/7-repressed genes transcription to regulate diverse biological functions (Fielitz et al, 2008;Jensen et al, 2009;Vega et al, 2004;Wang et al, 2008;Xu et al, 2007). We previously report that PKD1 activates both NF-κB and classical protein secretory pathway to modulate senescence-associated inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8) expressions and secretion thereby promoting cellular senescence (Su et al, 2018;Wang et al, 2014). However, whether PKD1 can regulate cellular senescence at epigenetic level remains unknown.…”