Dataset Information


Understanding the physiological role of asparaginyl endopeptidase (AEP)/Legumain

ABSTRACT: Understanding the regulation of lysosomal proteolytic/hidrolytic capacity has been recently advanced in a huge manner by the discovery of the lysosome-mTOR-TFEB pathway connecting nutrient sensing, autophagy and de novo lysosome generation. But, how lysosomes can adjust their proteolytic/hidrolytic capacity to meet varying conditions (more or less substrate) under normal fed conditions is not known. We have used AEP as a proxy to understand how lysosomes can compensate the lack of a key lysosomal protease to meet the requirements under physiological, fed conditions. To do this, we did compare cytoplasmic, membrane and nuclear fractions of WT and AEP MEFs that were expanded in SILAC media. AEP knock-out mice show pale kidney, with abnormal proliferation of the epithelial proximal tubular cells. In an attempt to understand the role of AEP in the kidney, we did compare kidney obtained from WT and AEP mice using kidneys from WT mice that were fed with SILAC food. Also, in an attempt to reproduce the changes observed in the absence of AEP in kidney and MEFs, we treated WT MEFs grown in SILAC media with MVO26630, specific inhibitor of AEP, for 12 and 48 hours.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast, Kidney

SUBMITTER: Jonathan Martinez Fabregas  

LAB HEAD: Colin Watts

PROVIDER: PXD011473 | Pride | 2019-01-09


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Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis.

Martínez-Fábregas Jonathan J   Prescott Alan A   van Kasteren Sander S   Pedrioli Deena Leslie DL   McLean Irwin I   Moles Anna A   Reinheckel Thomas T   Poli Valeria V   Watts Colin C  

Nature communications 20181217 1

Diverse cellular processes depend on the lysosomal protease system but how cells regulate lysosomal proteolytic capacity is only partly understood. We show here that cells can respond to protease/substrate imbalance in this compartment by de novo expression of multiple lysosomal hydrolases. This response, exemplified here either by loss of asparagine endopeptidase (AEP) or other lysosomal cysteine proteases, or by increased endocytic substrate load, is not dependent on the transcription factor E  ...[more]

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