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.