Klotho-mediated changes in the expression of Atg13 alter formation of ULK1 complex and thus initiation of ER- and Golgi-stress response mediated autophagy.
In the previous paper of our group, we have demonstrated that one of the crucial factors involved in the crosstalk between autophagy and apoptosis is klotho protein. We have shown that klotho silencing in normal human fibroblasts intensifies lipopolysaccharide (LPS)-induced p-eIF2a-mediated stress of endoplasmic reticulum and thus leads to retardation of prosurvival autophagy and induction of apoptotic cell death. In this study, we have performed a detailed step-by-step analysis of autophagy flux-related genes' expression and endoplasmic reticulum and Golgi stress related pathways in order to determine the exact mechanistic event when autophagy is inhibited in klotho-deficient cells on account of apoptosis initiation. We provide evidence that klotho-silencing in LPS-treated cells results in differential course of ER- and Golgi-mediated stress response. Further, we show that in klotho-deficient cells formation of ULK1 complex is inhibited and thus autophagy initiation is blocked on the account of apoptosis activation, while in the control cells cytoprotective autophagy is activated. Finally, in klotho-deficient cells formation of ULK1 complex is prevented by downregulated expression of Atg13. Thus, this study suggests a novel targeting pathway for efficient elimination of autophagy-deficient cells.
['Mytych|Jennifer|J|0000-0002-1265-973X', 'Sołek|Przemysław|P|', 'Będzińska|Agnieszka|A|', 'Rusinek|Kinga|K|', 'Warzybok|Aleksandra|A|', 'Tabęcka-Łonczyńska|Anna|A|', 'Koziorowski|Marek|M|']
D001343:Autophagy D000071189:Autophagy-Related Protein-1 Homolog D000071183:Autophagy-Related Proteins D004721:Endoplasmic Reticulum D059865:Endoplasmic Reticulum Stress D005347:Fibroblasts D005966:Glucuronidase D006056:Golgi Apparatus D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D000090265:Klotho Proteins D011485:Protein Binding D015398:Signal Transduction
Autophagy Klotho ER stress response Golgi stress response