The prolyl-specific peptidase fibroblast activation protein-α (FAP-α) is expressed at very low or undetectable levels in nondiseased human tissues but is selectively induced in activated (myo)fibroblasts at sites of tissue remodeling in fibrogenic processes. In normal regenerative processes involving transient fibrosis FAP-α⁺(myo)fibroblasts disappear from injured tissues, replaced by cells with a normal FAP-α^– phenotype. In chronic uncontrolled pathological fibrosis FAP-α⁺(myo)fibroblasts permanently replace normal tissues. The mechanisms of regulation and elimination of FAP-α expression in(myo)fibroblasts are unknown. According to a yeast two-hybrid screen and protein databanks search, we propose that the intracellular (co)-chaperone BAG6/BAT3 can interact with FAP-α, mediated by the BAG6/BAT3 Pro-rich domain, inducing proteosomal degradation of FAP-α protein under tissue homeostasis. In this Perspective, we discuss our findings in the context of current knowledge on the regulation of FAP-α expression and comment potential therapeutic strategies for uncontrolled fibrosis, including small molecule degraders (PROTACs)-modified FAP-α targeted inhibitors.

中文翻译：

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成纤维细胞活化蛋白-α 表达的调控：关注细胞内蛋白相互作用

脯氨酰特异性肽酶成纤维细胞活化蛋白-α (FAP-α) 在非患病人体组织中以非常低或检测不到的水平表达，但在纤维化过程中组织重塑部位的活化（肌）成纤维细胞中被选择性诱导。在涉及瞬时纤维化的正常再生过程中，FAP-α ⁺（肌）成纤维细胞从受损组织中消失，取而代之的是具有正常 FAP-α ^-表型的细胞。在慢性不受控制的病理性纤维化中 FAP-α ⁺（肌）成纤维细胞永久替代正常组织。（肌）成纤维细胞中 FAP-α 表达的调节和消除机制尚不清楚。根据酵母双杂交筛选和蛋白质数据库搜索，我们提出细胞内（共）伴侣蛋白 BAG6/BAT3 可以与 FAP-α 相互作用，由富含 BAG6/BAT3 Pro 的结构域介导，诱导 FAP-组织稳态下的α蛋白。在这个观点中，我们在 FAP-α 表达调节的当前知识背景下讨论我们的发现，并评论了不受控制的纤维化的潜在治疗策略，包括小分子降解剂 (PROTACs) 修饰的 FAP-α 靶向抑制剂。