PCDH17 regulates lysosomal degradative capacity to promote autophagy attenuation during prolonged starvation
Autophagy is induced by nutrient starvation to recycle intracellular constituents; however, its activity must subsequently be attenuated during prolonged nutrient deprivation. The mechanisms underlying this attenuation in mammalian cells remain incompletely understood. Here, using complementary HaloTag-based assays, we show that autophagic activity declines during prolonged starvation in HeLa…
Autophagy, a process that recycles intracellular constituents during nutrient starvation, must be regulated for prolonged starvation survival. Researchers used HaloTag-based assays and a genome-wide CRISPR/Cas9 knockout screen to investigate the mechanisms behind this attenuation in HeLa cells. The study discovered that protocadherin 17 (PCDH17) plays a role in autophagy attenuation during prolonged starvation.
Depleting PCDH17 maintained autophagic activity without affecting mTORC1 signaling, ULK1 abundance, or the initial stages of autophagosome formation. Instead, PCDH17 depletion increased lysosomal abundance, acidification, and proteolytic activity. The researchers identified a PCDH17 subpopulation associated with lysosomes, supplied mainly through the ER-Golgi pathway.
This pool undergoes proteolytic processing and lysosomal turnover, with starvation accelerating the degradation of the C-terminal fragment while preserving the more stable N-terminal fragment. The findings reveal that PCDH17 acts as an unexpected negative regulator of lysosomal function and highlights the importance of lysosomal degradative capacity in autophagy attenuation during prolonged starvation.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
