Chakraborthy Munmun, Rao Aparna
Hyderabad Eye Research Foundation (HERF), L.V. Prasad Eye Institute, Bhubaneswar 751024, Odisha, India.
School of Biotechnology, KIIT University, Bhubaneswar 751024, Odisha, India.
Curr Issues Mol Biol. 2023 Mar 13;45(3):2381-2392. doi: 10.3390/cimb45030154.
Autophagy is a cell's evolutionary conserved process for degrading and recycling cellular proteins and removing damaged organelles. There has been an increasing interest in identifying the basic cellular mechanism of autophagy and its implications in health and illness during the last decade. Many proteinopathies such as Alzheimer's and Huntington's disease are reported to be associated with impaired autophagy. The functional significance of autophagy in exfoliation syndrome/exfoliation glaucoma (XFS/XFG), remains unknown though it is presumed to be impaired autophagy to be responsible for the aggregopathy characteristic of this disease. In the current study we have shown that autophagy or ATG5 is enhanced in response to TGF-β1 in human trabecular meshwork (HTM) cells and TGF-β1 induced autophagy is necessary for increased expression of profibrotic proteins and epithelial to mesenchymal (EMT) through Smad3 that lead to aggregopathy. Inhibition of by siRNA mediated knockdown reduced profibrotic and EMT markers and increased protein aggregates in the presence of TGF-β1 stimulation. The miR-122-5p, which was increased upon TGF exposure, was also reduced upon inhibition. We thus conclude that TGF-β1 induces autophagy in primary HTM cells and a positive feedback loop exists between TGF-β1 and that regulated TGF downstream effects mainly mediated by Smad3 signaling with miR-122-5p also playing a role.
自噬是细胞进化上保守的过程，用于降解和循环利用细胞蛋白质并清除受损细胞器。在过去十年中，人们对确定自噬的基本细胞机制及其在健康和疾病中的意义越来越感兴趣。据报道，许多蛋白质病，如阿尔茨海默病和亨廷顿病，都与自噬受损有关。尽管推测自噬受损是剥脱综合征/剥脱性青光眼（XFS/XFG）聚集性病变特征的原因，但其在该病中的功能意义仍不清楚。在当前研究中，我们发现人小梁网（HTM）细胞中自噬或自噬相关蛋白5（ATG5）会因转化生长因子-β1（TGF-β1）而增强，且TGF-β1诱导的自噬对于通过Smad3增加促纤维化蛋白的表达以及上皮-间质转化（EMT）从而导致聚集性病变是必要的。在TGF-β1刺激下，通过小干扰RNA（siRNA）介导的敲低抑制ATG5可降低促纤维化和EMT标志物，并增加蛋白质聚集体。TGF暴露后增加的微小RNA-122-5p（miR-122-5p）在抑制ATG5后也减少。因此，我们得出结论，TGF-β1在原代HTM细胞中诱导自噬，并且TGF-β1与ATG5之间存在正反馈回路，该回路调节主要由Smad3信号介导的TGF下游效应，miR-122-5p也发挥作用。
