Autophagy Controls CSL/RBPJκ Stability through a p62/SQSTM1-Dependent Mechanism

• Published in: Cell reports (Cambridge) 2018-09, Vol.24 (12), p.3108-3114.e4
• Main Authors: Goruppi, Sandro, Jo, Seung-Hee, Laszlo, Csaba, Clocchiatti, Andrea, Neel, Victor, Dotto, G. Paolo
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; CAF; cancer-associated fibroblast; Cell Line; Cells, Cultured; CSL/RBPJκ; Down-Regulation; Fibroblasts - metabolism; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism; Mice; p62/SQSTM1; Protein Binding; Protein Stability; protein turnover; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; Signal Transduction; Skin Neoplasms - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.08.043

Cancer-associated fibroblasts (CAFs) are important at all tumor stages. CSL/RBPJκ suppresses the gene expression program leading to CAF activation and associated metabolic reprogramming, as well as autophagy. Little is known about CSL protein turnover, especially in the tumor microenvironment. We report that, in human dermal fibroblasts (HDFs), conditions inducing autophagy—often found in tumor stroma—down-regulate CSL protein levels but do not affect its mRNA levels. Genetic or pharmacologic targeting of the autophagic machinery blocks CSL down-modulation. Mechanistically, endogenous CSL associates with the autophagy and signaling adaptor p62/SQSTM1, which is required for CSL down-modulation by autophagy. This is functionally significant, because both CSL and p62 levels are lower in skin cancer-derived CAFs, in which autophagy is increased. Increasing cellular CSL levels stabilizes p62 and down-modulates the autophagic process. We reveal here an autophagy-initiated mechanism for CSL down-modulation, which could be targeted for stroma-focused cancer prevention and treatment. [Display omitted] •Autophagy down-modulates CSL/RBPJk in stromal fibroblasts•CSL degradation by autophagy requires interaction with p62 adaptor•CSL down-modulation by autophagy induces cancer-associated fibroblast (CAF) genes•CSL overexpression in CAFs stabilizes p62 and represses expression of autophagy genes Autophagic conditions are often found in the tumor stroma, where CSL/RBPJκ levels are down-modulated. Goruppi et al. identify a key role for autophagy in the degradation of CSL through a direct interaction with the p62 adaptor. This induces CSL-repressed genes involved in CAF activation and autophagy, linking the two processes.