SQSTM1的自噬降解使成纤维细胞活化，加速伤口愈合。

Autophagy Pub Date : 2025-05-31 DOI:10.1080/15548627.2025.2508546

Yujiao Xu, Xin Gu, Wenshu Li, Boyang Lin, Yiting Xu, Qingcheng Wei, Qingyuan Liu, Yamin Zhao, Rongzhuo Long, Hulin Jiang, Zhaoqiu Wu, Yunyao Liu, Lei Qiang

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引用次数: 0

摘要

伤口愈合是一个精心协调和复杂的过程，需要精确调节成纤维细胞的行为。巨噬/自噬是一种清除受损细胞成分的降解系统。SQSTM1/p62 （sequestosome 1）是一种完善的自噬受体，在自噬之外还作为信号中枢发挥作用。在这里，我们观察到成纤维细胞在受伤后自噬的显著上调。通过对Atg7（自噬相关7）特异性缺失的小鼠进行研究，我们发现成纤维细胞自噬控制伤口愈合。成纤维细胞自噬缺陷延迟了真皮修复，导致成纤维细胞增殖、迁移和肌成纤维细胞转化不足。体外实验进一步表明，自噬缺陷破坏了TGFB1（转化生长因子β 1）诱导的成纤维细胞增殖、迁移和肌成纤维细胞分化。机制上，自噬缺陷导致SMAD2 （SMAD家族成员2）和SMAD3在SQSTM1体内的隔离，并以依赖SQSTM1的方式减弱tgfb1诱导的受体调节的SMAD （R-SMAD）磷酸化。此外，sqstm1缺失挽救了自噬缺陷导致的皮肤伤口延迟愈合，自噬诱导剂以sqstm1依赖的方式促进伤口愈合。我们的研究结果强调了成纤维细胞自噬在伤口愈合中的关键作用，并阐明了自噬调节成纤维细胞行为的潜在机制。

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Autophagic degradation of SQSTM1 enables fibroblast activation to accelerate wound healing.

Wound healing is a meticulously coordinated and intricate progression that necessitates precise regulation of fibroblast behavior. Macroautophagy/autophagy is a degradation system for clearing damaged cellular components. SQSTM1/p62 (sequestosome 1), a well-established autophagy receptor, also functions as a signaling hub beyond autophagy. Here, we observed a significant upregulation of autophagy in fibroblasts after wounding. Using mice with fibroblast-specific deletion of Atg7 (autophagy related 7), we found that fibroblast autophagy governed wound healing. Fibroblast autophagy deficiency delayed proper dermal repair that was mired in insufficient fibroblast proliferation, migration, and myofibroblast transition. In vitro experiments further revealed that autophagy deficiency disrupted TGFB1 (transforming growth factor beta 1)-induced fibroblast proliferation, migration, and myofibroblast differentiation. Mechanistically, autophagy deficiency led to SMAD2 (SMAD family member 2) and SMAD3 sequestration within SQSTM1 bodies and attenuated TGFB1-induced receptor-regulated SMAD (R-SMAD) phosphorylation in an SQSTM1-dependent manner. Furthermore, sqstm1 deletion rescued the delayed skin wound healing caused by autophagy deficiency, and autophagy inducers promoted wound healing in an SQSTM1-dependent manner. Our findings highlight the critical role of fibroblast autophagy in wound healing and elucidate the underlying mechanisms by which autophagy regulates fibroblast behavior.Abbreviation: 3-MA: 3-methyladenine; ACTA2/α-SMA: actin alpha 2, smooth muscle; ACTB: actin beta; AMPK: AMP-activated protein kinase; ATG: autophagy related; BiFC: bimolecular fluorescence complementation; COL1A2: collagen type I alpha 2 chain; ECM: extracellular matrix; FGF: fibroblast growth factor; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HDF: human dermal fibroblast; HVGs: highly variable genes; KO: knockout; LMNB1: lamin B1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67/Ki-67: marker of proliferation Ki-67; MTOR/mTOR: mechanistic target of rapamycin kinase; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NFKB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; PCA: principal component analysis; PI3K: phosphoinositide 3-kinase; R-SMAD: receptor-regulated SMAD; SBE: SMAD binding element; shCON: small hairpin negative control; siNC: negative control; siRNA: small interfering RNA; SMAD: SMAD family member; SQSTM1/p62: sequestosome 1; ssGSEA: single-sample gene set enrichment analysis; TGFB/TGF-β: transforming growth factor beta; TGFBR1: transforming growth factor beta receptor 1; TGFBR2: transforming growth factor beta receptor 2; VIM: vimentin; WT: wild-type; ZFYVE9/SARA: zinc finger FYVE-type containing 9.

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Autophagy

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