ArticleThe Journal of clinical investigation2016
Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Differential Gene Expression in Synovium Between Male and Female Knee Osteoarthritis.Medicina (Kaunas, Lithuania) · 2026Article
- Mitochondria-Associated Endoplasmic Reticulum Membrane Biomarkers in Coronary Heart Disease and Atherosclerosis: A Transcriptomic and Mendelian Randomization Study.Current issues in molecular biology · 2026Article
- The role of splicing events in the inflammatory response of atherosclerosis: molecular mechanisms and modulation.Frontiers in immunology · 2024Review
- Calpain and Cardiometabolic Diseases.International journal of molecular sciences · 2023Review
- The miR-21-5p enriched in the apoptotic bodies of M2 macrophage-derived extracellular vesicles alleviates osteoarthritis by changing macrophage phenotype.Genes & diseases · 2023Article
- A calpain-6/YAP axis in sarcoma stem cells that drives the outgrowth of tumors and metastases.Cell death & disease · 2022Article
- Calpain-mediated proteolytic production of free amino acids in vascular endothelial cells augments obesity-induced hepatic steatosis.The Journal of biological chemistry · 2022Article
- Thirty-Five-Year History of Desialylated Lipoproteins Discovered by Vladimir Tertov.Biomedicines · 2022Review
- Pinocytotic engulfment of lipoproteins by macrophages.Frontiers in cardiovascular medicine · 2022Review
- Effects of functionally diverse calpain system on immune cells.Immunologic research · 2021Review
- Hypercholesterolemia and Lymphatic Defects: The Chicken or the Egg?Frontiers in cardiovascular medicine · 2021Review
- CAPN6 in disease: An emerging therapeutic target (Review).International journal of molecular medicine · 2020Review
- Article
- Calpain proteolytic systems counteract endothelial cell adaptation to inflammatory environments.Inflammation and regeneration · 2020Review
- Deficiency of calpain-6 inhibits primary ciliogenesis.BMB reports · 2019Article
- Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence.JCI insight · 2018Article
- Dysregulation of Calpain Proteolytic Systems Underlies Degenerative Vascular Disorders.Journal of atherosclerosis and thrombosis · 2018Review
- Emerging roles of calpain proteolytic systems in macrophage cholesterol handling.Cellular and molecular life sciences : CMLS · 2017Review
- Defective Protein Catabolism in Atherosclerotic Vascular Inflammation.Frontiers in cardiovascular medicine · 2017Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Macrophages contribute to the development of atherosclerosis through pinocytotic deposition of native LDL-derived cholesterol in macrophages in the vascular wall. Inhibiting macrophage-mediated lipid deposition may have protective effects in atheroprone vasculature, and identifying mechanisms that potentiate this process may inform potential therapeutic interventions for atherosclerosis. Here, we report that dysregulation of exon junction complex-driven (EJC-driven) mRNA splicing confers hyperpinocytosis to macrophages during atherogenesis. Mechanistically, we determined that inflammatory cytokines induce an unconventional nonproteolytic calpain, calpain-6 (CAPN6), which associates with the essential EJC-loading factor CWC22 in the cytoplasm. This association disturbs the nuclear localization of CWC22, thereby suppressing the splicing of target genes, including those related to Rac1 signaling. CAPN6 deficiency in LDL receptor-deficient mice restored CWC22/EJC/Rac1 signaling, reduced pinocytotic deposition of native LDL in macrophages, and attenuated macrophage recruitment into the lesions, generating an atheroprotective phenotype in the aorta. In macrophages, the induction of CAPN6 in the atheroma interior limited macrophage movements, resulting in a decline in cell clearance from the lesions. Consistent with this finding, we observed that myeloid CAPN6 contributed to atherogenesis in a murine model of bone marrow transplantation. Furthermore, macrophages from advanced human atheromas exhibited increased CAPN6 induction and impaired CWC22 nuclear localization. Together, these results indicate that CAPN6 promotes atherogenicity in inflamed macrophages by disturbing CWC22/EJC systems.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.