State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Autophagy. 2021 Aug;17(8):1873-1888. doi: 10.1080/15548627.2020.1796015. Epub 2020 Aug 2.
UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, is widely expressed in diverse human and mouse tissues and is more abundant in retina and kidney. However, the functional characterization of UXT at tissue level was largely unknown. Here, we reported that mice deficient in UXT exhibited salient features of retinal degenerative disease, similar to retinitis pigmentosa. Conditional knockout (CKO) of led to retinal degeneration and pigmentation in mice retina along with significant alterations of retinitis pigmentosa-related genes, which indicated UXT might be associated with retinal degenerative disease sharing key features to retinitis pigmentosa. Consistently, the electroretinogram (ERG) responses were dramatically impaired in CKO retinas. Strong degenerative features were observed in CKO retinas, including specific and progressive reduction of photoreceptor cells and increased numbers of apoptotic cells. Intriguingly, macroautophagic/autophagic flux was enhanced in CKO retina. Mechanistically, we found UXT was indispensable to suppress photoreceptor apoptotic cell death by inhibiting autophagy through regulating the activity of MTOR (mechanistic target of rapamycin kinase), a key negative regulator of autophagy. Conversely, knockdown of UXT induced the robust expression of the canonical autophagy-related genes and boosted autophagic flux and apoptosis, finally resulting in severe retina degeneration in CKO mice. Taken together, our study reveals a vital role of UXT in preventing retina from degeneration. The loss of UXT results in a hyper-autophagic state leading to massive retinal degeneration. Therefore, UXT may be a crucial target for retinal degenerative disease.: 3-ma: 3-methyladenine; casp3: caspase 3; cko: conditional knockout; erg: electroretinogram; gapdh: glyceraldehyde-3-phosphate dehydrogenase; map1lc3b/lc3b: microtubule-associated protein 1 light chain 3; mtor: mechanistic target of rapamycin kinase; parp: poly (adp-ribose) polymerase family; rna-seq: rna sequencing; rp: retinitis pigmentosa; rps6kb1/s6k: ribosomal protein s6 kinase b1; sqstm1: sequestosome 1; tunel: terminal deoxynucleotidyl transferase mediated dutp nick-end labeling; uxt: ubiquitously expressed prefoldin like chaperone.
UXT（普遍表达的前折叠体样伴侣）是一种小型伴侣样蛋白，广泛表达于各种人和鼠组织中，在视网膜和肾脏中更为丰富。然而，UXT 在组织水平的功能特征在很大程度上仍是未知的。在这里，我们报道了 UXT 缺失的小鼠表现出明显的视网膜退行性疾病特征，类似于色素性视网膜炎。导致视网膜变性和色素沉着，同时伴随着与色素性视网膜炎相关基因的显著改变，这表明 UXT 可能与具有与色素性视网膜炎关键特征的视网膜退行性疾病有关。一致地，电生理视网膜电图 (ERG) 反应在 CKO 视网膜中明显受损。在 CKO 视网膜中观察到强烈的退行性特征，包括光感受器细胞的特异性和进行性减少以及凋亡细胞数量的增加。有趣的是，在 CKO 视网膜中观察到巨自噬/自噬通量增强。在机制上，我们发现 UXT 通过调节 MTOR（雷帕霉素靶蛋白激酶）的活性，是自噬的关键负调控因子，对于抑制光感受器细胞凋亡是不可或缺的，从而抑制自噬。相反，UXT 的敲低诱导了经典自噬相关基因的强烈表达，并促进了自噬通量和凋亡，最终导致 CKO 小鼠严重的视网膜变性。总之，我们的研究揭示了 UXT 在防止视网膜变性中的重要作用。UXT 的缺失导致自噬过度活跃，导致大量视网膜变性。因此，UXT 可能是视网膜退行性疾病的关键靶点。3-ma：3-甲基腺嘌呤；casp3：半胱天冬酶 3；cko：条件性敲除；erg：视网膜电图；gapdh：甘油醛-3-磷酸脱氢酶；map1lc3b/lc3b：微管相关蛋白 1 轻链 3；mtor：雷帕霉素靶蛋白激酶；parp：多聚（ADP-核糖）聚合酶家族；rna-seq：rna 测序；rp：色素性视网膜炎；rps6kb1/s6k：核糖体蛋白 s6 激酶 b1；sqstm1：自噬体相关蛋白 1；tunel：末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记；uxt：普遍表达的前折叠体样伴侣。
