BAG2 (BCL2 associated athanogene 2) is associated with cell fate determination in response to various pathological conditions. However, the effects of BAG2 on M. tuberculosis-induced endoplasmic reticulum (ER) stress remain elusive. Herein, we report that M. tuberculosis infection of macrophages triggered ER stress and downregulated BAG2 expression. Overexpression of BAG2 enhanced autophagic flux and activated macroautophagy/autophagy targeted to the ER (reticulophagy). In addition, through increasingly localizing SQSTM1 to the ER in BAG2-overexpressing macrophages, we found that the autophagy receptor protein SQSTM1/p62 (sequestosome 1) is associated with the BAG2-induced reticulophagy. Our data also confirmed that BAG2 could render cells resistant to M. tuberculosis-induced cellular damage, and the anti-apoptotic effects of BAG2 in M. tuberculosis-treated macrophages were partially abolished by the autophagic flux inhibitor bafilomycin A₁. Furthermore, the dissociation of BECN1 and BCL2 mediated by activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) was responsible for BAG2-activated autophagy. In addition, XBP1 downstream of the ERN1/IRE1 signaling pathway was bound to the Bag2 promoter region and transcriptionally inhibited BAG2 expression. Collectively, these results indicated that BAG2 has anti-apoptotic effects on M. tuberculosis-induced ER stress, which is dependent on the promotion of autophagic flux and the induction of selective autophagy. We revealed a potential host defense mechanism that links BAG2 to ER stress and autophagy during M. tuberculosis infection.

Abbreviations

ATF6: activating transcription factor 6; BECN1: beclin 1; Baf A1: bafilomycin A₁; CASP3: caspase 3; DDIT3/CHOP/GADD153: DNA damage inducible transcript 3; DAPI: 4ʹ,6-diamidino-2-phenylindole; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; HSPA5/GRP78/BiP: heat shock protein 5; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; SQSTM1/p62: sequestosome 1; UPR: unfolded protein response; XBP1: x-box binding protein 1

中文翻译：

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BAG2通过选择性自噬改善了内质网应激诱导的结核分枝杆菌感染的巨噬细胞的细胞凋亡。

BAG2（BCL2相关的致癌基因2）与细胞命运的确定相关，并响应各种病理状况。但是，BAG2对结核分枝杆菌诱导的内质网（ER）应激的影响仍然难以捉摸。在本文中，我们报道结核分枝杆菌感染巨噬细胞触发内质网应激和下调BAG2表达。BAG2的过表达增强了自噬通量，并激活了针对ER（网状吞噬）的宏观自噬/自噬。此外，通过将SQSTM1越来越多地定位于过表达BAG2的巨噬细胞中的ER，我们发现自噬受体蛋白SQSTM1 / p62（sequestosome 1）与BAG2诱导的网状细胞形成有关。我们的数据还证实BAG2可以使细胞对结核分枝杆菌具有抗性自噬通量抑制剂bafilomycin A ₁消除了BAG2诱导的细胞损伤以及BAG2在结核分枝杆菌治疗的巨噬细胞中的抗凋亡作用。此外，由丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）活化介导的BECN1和BCL2的解离是BAG2活化自噬的原因。此外，ERN1 / IRE1信号通路下游的XBP1与Bag2启动子区域结合，并在转录上抑制BAG2表达。总的来说，这些结果表明BAG2对结核分枝杆菌具有抗凋亡作用。诱导的内质网应激，这取决于自噬通量的促进和选择性自噬的诱导。我们揭示了一种潜在的宿主防御机制，该机制将BAG2与结核分枝杆菌感染期间的内质网应激和自噬相联系。

缩略语

ATF6：激活转录因子6；BECN1：beclin 1；Baf A1：bafilomycin A ₁；CASP3：胱天蛋白酶3；DDIT3 / CHOP / GADD153：DNA损伤诱导转录本3；DAPI：4ʹ，6-二mid基-2-苯基吲哚; EIF2AK3 / PERK：真核翻译起始因子2α激酶3；ER：内质网；ERN1 / IRE1：内质网至细胞核的信号传导1；HSPA5 / GRP78 / BiP：热激蛋白5；MAP1LC3B / LC3B：微管相关蛋白1轻链3 beta；MAPK / ERK：有丝分裂原激活的蛋白激酶；SQSTM1 / p62：螯合体1；UPR：展开的蛋白质反应；XBP1：x-box结合蛋白1