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RAB11FIP3可变剪接异常导致糖尿病足溃疡功能障碍。

Disrupted Alternative Splicing of RAB11FIP3 Contributes to Diabetic Foot Ulcer Dysfunction.

作者信息

Zhu Dong, Chen Feifei, Li Xiaoyue, Ning Qianqian, Wang Jian, Wei Wuhan, Zhang Jingyu, Shen Caiqi, Sun Lili, Gao Jiawen, Wang Ziyi, Liu Yuting, Zhang Aijun, Li Qiang, Jin Peisheng

机构信息

Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.

Xuzhou Medical University, Xuzhou, China.

出版信息

J Cell Mol Med. 2025 Aug;29(15):e70663. doi: 10.1111/jcmm.70663.

DOI:10.1111/jcmm.70663
PMID:40758539
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12320866/
Abstract

Dysregulation of alternative splicing (AS) has been associated with various complications of diabetes, yet its role in the pathogenesis of diabetic foot ulcers (DFUs) and its involvement in metabolic memory (MM) remain unclear. In this study, we identified specific AS events in RAB11FIP3, notably the full-length (RAB11FIP3-FL) isoform and exon 6 exclusion (RAB11FIP3-Δ6). We found that RAB11FIP3 (FL/Δ6) ratio is significantly elevated in patients with MM and DFUs. Additionally, we demonstrated that knockdown of RAB11FIP3-FL alleviates vascular endothelial damage associated with MM and enhances DFU healing. Furthermore, we identified that HNRNPL promotes the retention of exon 6 in RAB11FIP3-FL, thereby increasing the FL/Δ6 ratio. Mechanistically, our results show that RAB11FIP3-FL promotes the ubiquitination and degradation of HIF-1α through NEDD4L, independent of VHL. In conclusion, our study identifies RAB11FIP3-FL as a pathogenic splicing isoform contributing to impaired DFU healing. Knockdown of RAB11FIP3-FL promotes vascular regeneration and accelerates diabetic wound healing, offering new therapeutic targets for DFU treatment.

摘要

可变剪接（AS）失调与糖尿病的多种并发症相关，但其在糖尿病足溃疡（DFU）发病机制中的作用及其与代谢记忆（MM）的关系仍不清楚。在本研究中，我们鉴定了RAB11FIP3中的特定AS事件，特别是全长（RAB11FIP3-FL）异构体和外显子6缺失（RAB11FIP3-Δ6）。我们发现，MM和DFU患者的RAB11FIP3（FL/Δ6）比值显著升高。此外，我们证明敲低RAB11FIP3-FL可减轻与MM相关的血管内皮损伤并促进DFU愈合。此外，我们确定HNRNPL促进RAB11FIP3-FL中外显子6的保留，从而增加FL/Δ6比值。从机制上讲，我们的结果表明，RAB11FIP3-FL通过NEDD4L促进HIF-1α的泛素化和降解，不依赖于VHL。总之，我们的研究确定RAB11FIP3-FL是一种致病性剪接异构体，导致DFU愈合受损。敲低RAB11FIP3-FL可促进血管再生并加速糖尿病伤口愈合，为DFU治疗提供了新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/80c78dd32aab/JCMM-29-e70663-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/4ddd2db60991/JCMM-29-e70663-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/7206ffe02516/JCMM-29-e70663-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/e589e86b1801/JCMM-29-e70663-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/ec7709d2fda7/JCMM-29-e70663-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/9425a0e67045/JCMM-29-e70663-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/19744ebf17e7/JCMM-29-e70663-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/80c78dd32aab/JCMM-29-e70663-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/4ddd2db60991/JCMM-29-e70663-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/7206ffe02516/JCMM-29-e70663-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/3dc2291deab3/JCMM-29-e70663-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/e589e86b1801/JCMM-29-e70663-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/ec7709d2fda7/JCMM-29-e70663-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/9425a0e67045/JCMM-29-e70663-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/19744ebf17e7/JCMM-29-e70663-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85cc/12320866/80c78dd32aab/JCMM-29-e70663-g002.jpg

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