Fig. 6

Schematic illustration of the biological mechanisms underlying STING activation, autophagy, and TFEB nuclear localization in conventional PEComas. Still partially unknown stimuli, such as mitochondrial damage and/or crosstalk with the MTORC1 signaling (dotted arrows), cause dsDNA cytoplasmic accumulation and cGAMP formation via cGAS, triggering STING. Among its various downstream pathways, STING prompts the autophagy process through the lipidation of key phagosome proteins, such as LC3B and those of the GABARAPs family. Once modified, these latter can sequester the FNIP/FLCN molecules from the MTORC1 complex, hyper-activated due to TSC1/TSC2 mutations, preventing it from phosphorylating the TFEB and MITF transcriptional factors but without altering its kinase activity. Thus, rescued from ubiquitin-dependent proteasome degradation, TFEB/MITF may move to the nucleus, where they can enhance the transcription of key genes involved in autophagosome and lysosome biogenesis. mtDNA: mitochondrial DNA, dsDNA: double-stranded DNA.