| First Author | Hou Y | Year | 2022 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 14 |
| Issue | 2 | Pages | 375-403 |
| PubMed ID | 35643234 | Mgi Jnum | J:339411 |
| Mgi Id | MGI:7312288 | Doi | 10.1016/j.jcmgh.2022.05.006 |
| Citation | Hou Y, et al. (2022) Epithelial SMYD5 Exaggerates IBD by Downregulating Mitochondrial Functions via Post-Translational Control of PGC-1alpha Stability. Cell Mol Gastroenterol Hepatol |
| abstractText | BACKGROUND & AIMS: The expression and role of methyltransferase SET and MYND domain-containing protein 5 (SMYD5) in inflammatory bowel disease (IBD) is completely unknown. Here, we investigated the role and underlying mechanism of epithelial SMYD5 in IBD pathogenesis and progression. METHODS: The expression levels of SMYD5 and the mitochondrial transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) were examined by Western blot, immunofluorescence staining, and immunohistochemistry in intestinal epithelial cells (IECs) and in colon tissues from human IBD patients and colitic mice. Mice with Smyd5 conditional knockout in IECs and littermate controls were subjected to dextran sulfate sodium-induced colitis and the disease severity was assessed. SMYD5-regulated mitochondrial biogenesis was examined by quantitative reverse-transcription polymerase chain reaction and transmission electron microscopy, and the mitochondrial oxygen consumption rate was measured in a Seahorse Analyzer system. SMYD5 and PGC-1alpha interaction was determined by co-immunoprecipitation assay. PGC-1alpha degradation and turnover (half-life) were analyzed by cycloheximide chase assay. SMYD5-mediated PGC-1alpha methylation was assessed via in vitro methylation assay followed by mass spectrometry for identification of methylated lysine residues. RESULTS: Up-regulated SMYD5 and down-regulated PGC-1alpha were observed in intestinal epithelia from IBD patients and colitic mice. Smyd5 depletion in IECs protected mice from dextran sulfate sodium-induced colitis. SMYD5 was critically involved in regulating mitochondrial biology such as mitochondrial biogenesis, respiration, and apoptosis. Mechanistically, SMYD5 regulates mitochondrial functions in a PGC-1alpha-dependent manner. Furthermore, SMYD5 mediates lysine methylation of PGC-1alpha and subsequently facilitates its ubiquitination and degradation. CONCLUSIONS: SMYD5 attenuates mitochondrial functions in IECs and promotes IBD progression by enhancing PGC-1alpha degradation in a methylation-dependent manner. Strategies to decrease SMYD5 expression and/or increase PGC-1alpha expression in IECs might be a promising therapeutic approach to treat IBD patients. |
