Dysfunction of lysosomes partakes the onset of multiple human pathologies. Even though the activity of lysosomal hydrolases was considered confined to the lysosomal lumen for more than 50 years, nowadays we know they localise in the nuclear and cytosolic compartment. These extra-lysosomal activities have exponentially increased the number of biological processes controlled by lysosomes and their potential contribution to the onset and progression of human diseases. Thus, a deeper understanding of the signalling pathways involved in the regulation of lysosomes would provide new tools to ameliorate the symptoms associated with these diseases.
Lysosomes are the recycling plants of cells, but additionally take part in diverse features of cell life. Therefore, there is a strong interest in understanding the mechanisms that control its activity. The discovery of the role played by the mTOR-TFEB axis during starvation served to unveil partially the regulation of lysosomal gene expression. However, as recently shown by the researcher and others, the cytokines-STAT3 axis is also important to lysosomal governance. However, the molecular mechanisms of the cytokine-mediated lysosomal regulation remain unresolved.
CytoLysoReg implementation has served to unveil kinetic differences between the IL-6 and IL-10 signalling networks explaining the ability of IL-6 to induce the expression of lysosomal proteases, contrary to IL-10. First difference is the transient activation of STAT3 and STAT1 by IL-6 vs. persistent STAT3 activation and lack of STAT1 activation by IL-10. The second, a sustained activation of STAT3 obtained with IL-6 not elicited by IL-10. However, it falls short to explain the molecular mechanism through which IL-10 inhibits their expression. Then, our phospho-proteomics approach has allowed us to dig deeper in the differences between these two cytokines. Meanwhile, IL-6 induces the phosphorylation and activation of signalling pathways and proteins regulating transcription, gene expression and proliferation, therefore further enhancing the expression of these lysosomal proteases; IL-10 inhibits these pathways thus explaining the inhibitory effect of IL-10 on lysosomal activity. This information provides us with novel targets involved in the cytokine-mediated regulation of the lysosomal compartment, thus offering new tools to fine-tune lysosomal activity.
On the other hand, Oncostatin M—a member of the IL-6 cytokine-family—has been shown to regulate LM-PCD through STAT3. Notably, recent data link STAT3 to the upkeep of lysosomal homeostasis without LM-PCD induction. However, the molecular mechanisms explaining this dichotomic behaviour of STAT3 have not been elucidated. Through CytoLysoReg implementation we are currently generating a phospho-proteomic dataset comparing the signalling pathways and biological processes regulated during LM-PCD and lysosomal homeostatic response that will allow us to unveil how STAT3 can switch between a pro-survival factor controlling lysosomal homeostasis and a trigger of LM-PCD
