UVA causes dual inactivation of cathepsin B and L underlying lysosomal dysfunction in human dermal fibroblasts

Sarah D. Lamore, Georg T. Wondrak

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Cutaneous exposure to chronic solar UVA-radiation is a causative factor in photocarcinogenesis and photoaging. Recently, we have identified the thiol-dependent cysteine-protease cathepsin B as a novel UVA-target undergoing photo-oxidative inactivation upstream of autophagic-lysosomal dysfunction in fibroblasts. In this study, we examined UVA effects on a wider range of cathepsins and explored the occurrence of UVA-induced cathepsin inactivation in other cultured skin cell types. In dermal fibroblasts, chronic exposure to non-cytotoxic doses of UVA caused pronounced inactivation of the lysosomal cysteine-proteases cathepsin B and L, effects not observed in primary keratinocytes and occurring only to a minor extent in primary melanocytes. In order to determine if UVA-induced lysosomal impairment requires single or dual inactivation of cathepsin B and/or L, we used a genetic approach (siRNA) to selectively downregulate enzymatic activity of these target cathepsins. Monitoring an established set of protein markers (including LAMP1, LC3-II, and p62) and cell ultrastructural changes detected by electron microscopy, we observed that only dual genetic antagonism (targeting both CTSB and CTSL expression) could mimic UVA-induced autophagic-lysosomal alterations, whereas single knockdown (targeting CTSB or CTSL only) did not display 'UVA-mimetic' effects failing to reproduce the UVA-induced phenotype. Taken together, our data demonstrate that chronic UVA inhibits both cathepsin B and L enzymatic activity and that dual inactivation of both enzymes is a causative factor underlying UVA-induced impairment of lysosomal function in dermal fibroblasts.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalJournal of Photochemistry and Photobiology B: Biology
Volume123
DOIs
StatePublished - Jun 5 2013

Keywords

  • Cathepsin B
  • Cathepsin L
  • Fibroblast
  • UVA Skin photodamage

ASJC Scopus subject areas

  • Radiation
  • Radiological and Ultrasound Technology
  • Biophysics
  • Radiology Nuclear Medicine and imaging

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