Nirmal Robinson
Lysosome biogenesis in macrophages and tissue repair during infection
Autophagy encompasses autophagosome formation and the fusion of the phagophore
with lysosomes (autophagic flux). The molecular pathways that govern these
processes are well described to regulate tissue regeneration, repair and longevity in
various animal models. Sirt1 is a lysine deacetylase known to positively regulate
autophagy. However, Sirt1-independent autophagy upon rapamycin treatment has
also been described. Surprisingly, we found that loss of Sirt1 under basal conditions
leads to enhanced translocation of TFEB into nucleus thereby enhancing lysosome
biogenesis and autophagic flux. Increased TFEB-translocation is a result of
proteosomal degradation of mTOR and increased AMPK activation. Interestingly,
these mechanisms are evolutionarily conserved in C. elegans. In an infection setting
we show that, mice deficient for Sirt1 in the myeloid compartment (Srit1fl/fl LysMCre)
exhibit lesser tissue damage and better protection. TFEB is a transcriptional regulator
of autophagy. Our studies have also shown that TFEB could alternatively play a
transcription independent function and thereby regulate cell proliferation.