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

• Published in: Nature communications 2018-12, Vol.9 (1), p.5343-16, Article 5343
• Main Authors: Martínez-Fábregas, Jonathan, Prescott, Alan, van Kasteren, Sander, Pedrioli, Deena Leslie, McLean, Irwin, Moles, Anna, Reinheckel, Thomas, Poli, Valeria, Watts, Colin
• Format: Article
• Language: English
• Subjects: 13; 13/95; 38/39; 631/45/607/468; 631/80/642/1624; 82/58; Activation; Adaptation; Animals; Antigens; Asparagine; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Cell Line; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Cysteine Proteases - genetics; Cysteine Proteases - metabolism; Disease; Endopeptidases; Fibroblasts; Gene expression; Homeostasis; Humanities and Social Sciences; Humans; Janus Kinase 2 - genetics; Kidney diseases; Kidney Diseases - genetics; Kidney Diseases - pathology; Kidneys; Life sciences; Lysosomal Storage Diseases - genetics; Lysosomal Storage Diseases - pathology; Lysosomes - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Oxidative stress; Oxidative Stress - physiology; Protease; Proteins; Proteolysis; RNA Interference; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Splenomegaly; Stat3 protein; STAT3 Transcription Factor - genetics; Substrates; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07741-6

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. How cells regulate their lysosomal proteolytic capacity is only partly understood. Here, the authors show that lysosomal protease deficiency or substrate overload induces lysosomal stress leading to activation of a STAT3-dependent, TFEB-independent pathway of lysosomal hydrolase expression.