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

Jonathan Martinez-Fabregas (Lead / Corresponding author), Alan Prescott, Sander van Kasteren, Deena Leslie Pedrioli, William McLean, Anna Moles, Thomas Reinheckel, Valeria Poli, Colin Watts (Lead / Corresponding author)

Research output: Contribution to journalArticle

2 Citations (Scopus)
51 Downloads (Pure)

Abstract

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 EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under ‘fed’ rather than ‘starved’ conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.
Original languageEnglish
Article number5343
Pages (from-to)1-16
Number of pages16
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 17 Dec 2018

Fingerprint

homeostasis
protease
Oxidative stress
Endopeptidases
Oxidative Stress
Homeostasis
Peptide Hydrolases
Asparagine
Transcription Factors
Substrates
Chemical activation
mice
Cysteine Proteases
kidney diseases
cells
activation
Hydrolases
cysteine
Splenomegaly
Kidney Diseases

Cite this

@article{d6bbd499e74b4dab9885f02bf43541f1,
title = "Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis",
abstract = "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 EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under ‘fed’ rather than ‘starved’ conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.",
author = "Jonathan Martinez-Fabregas and Alan Prescott and {van Kasteren}, Sander and {Leslie Pedrioli}, Deena and William McLean and Anna Moles and Thomas Reinheckel and Valeria Poli and Colin Watts",
year = "2018",
month = "12",
day = "17",
doi = "10.1038/s41467-018-07741-6",
language = "English",
volume = "9",
pages = "1--16",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis. / Martinez-Fabregas, Jonathan (Lead / Corresponding author); Prescott, Alan; van Kasteren, Sander; Leslie Pedrioli, Deena; McLean, William; Moles, Anna; Reinheckel, Thomas; Poli, Valeria; Watts, Colin (Lead / Corresponding author).

In: Nature Communications, Vol. 9, No. 1, 5343, 17.12.2018, p. 1-16.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis

AU - Martinez-Fabregas, Jonathan

AU - Prescott, Alan

AU - van Kasteren, Sander

AU - Leslie Pedrioli, Deena

AU - McLean, William

AU - Moles, Anna

AU - Reinheckel, Thomas

AU - Poli, Valeria

AU - Watts, Colin

PY - 2018/12/17

Y1 - 2018/12/17

N2 - 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 EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under ‘fed’ rather than ‘starved’ conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.

AB - 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 EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under ‘fed’ rather than ‘starved’ conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.

UR - http://www.scopus.com/inward/record.url?scp=85058772846&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07741-6

DO - 10.1038/s41467-018-07741-6

M3 - Article

VL - 9

SP - 1

EP - 16

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5343

ER -