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

Paper ID Volume ID Publish Year Pages File Format Full-Text
30583 44489 2013 12 PDF Available
Title
UVA causes dual inactivation of cathepsin B and L underlying lysosomal dysfunction in human dermal fibroblasts
Abstract

•UVA selectively inactivates lysosomal cysteine-proteases (cathepsin B and L).•Chronic UVA causes lysosomal dysfunction in skin fibroblasts.•Dual genetic antagonism (siCTSB/CTSL) mimics UVA-induced lysosomal alterations.•Single knockdown (siCTSB or siCTSL only) does not display ‘UVA-mimetic’ effects.•Cathepsin B/L dual inactivation is a causative factor in lysosomal impairment by UVA.

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.

Keywords
UVA; Skin photodamage; Cathepsin B; Cathepsin L; Fibroblast
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UVA causes dual inactivation of cathepsin B and L underlying lysosomal dysfunction in human dermal fibroblasts
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Publisher
Database: Elsevier - ScienceDirect
Journal: Journal of Photochemistry and Photobiology B: Biology - Volume 123, 5 June 2013, Pages 1–12
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us