RT Journal Article
SR Electronic
T1 Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.04.425106
DO 10.1101/2021.01.04.425106
A1 Suprit Gupta
A1 Julian Yano
A1 Htet Htwe Htwe
A1 Hijai R. Shin
A1 Zeynep Cakir
A1 Thomas Ituarte
A1 Kwun W. Wen
A1 Grace E. Kim
A1 Roberto Zoncu
A1 David W. Dawson
A1 Rushika M. Perera
YR 2021
UL http://biorxiv.org/content/early/2021/01/04/2021.01.04.425106.abstract
AB Lysosomes must maintain integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but whether dedicated programs for maintaining lysosomal membrane integrity facilitate pancreatic cancer growth is unknown. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor, Myoferlin, as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosome localization of Myoferlin is necessary and sufficient for maintenance of lysosome health and provides an early-acting protective system against membrane damage that is independent from the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival, and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances pro-oncogenic activities of the lysosome.Competing Interest StatementThe authors have declared no competing interest.