a Section of Molecular Biology, Division of Biological Sciences , University of California , San Diego , CA , USA.
Autophagy. 2018;14(9):1574-1585. doi: 10.1080/15548627.2018.1463120. Epub 2018 Aug 21.
TRIM37 gene mutations cause mulibrey (muscle-liver-brain-eye) nanism, a severe growth disorder with prenatal onset. Although TRIM37 depletion normally induces apoptosis, patients with TRIM37 mutations have a high risk of developing tumors, suggesting that there may be an alternative pro-survival mechanism for TRIM37-deficient tumor cells. We find that TRIM37 interacts with MTOR and RRAGB proteins, enhances the MTOR-RRAGB interaction and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. In response to loss of TRIM37 functions, phosphorylation of TFEB is significantly reduced, resulting in its translocation into the nucleus enabling its transcriptional activation of genes involved in lysosome biogenesis and macroautophagy/autophagy. The enhanced autophagy depends on the inhibition of MTORC1 signaling and may serve as an alternative mechanism to survive the loss of TRIM37 functions. Our study unveils a positive role of TRIM37 in regulating the MTORC1-TFEB axis and provides mechanistic insights into the pathogenesis of mulibrey nanism, as well as potential therapeutic treatment.
ACTB: actin beta; ATG: autophagy related; CASP3: caspase3; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; CTS: cathepsin proteases; CTSL: cathepsin L; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LMNB1: lamin B1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; mulibrey: muscle-liver-brain-eye; NAC: N-acetyl-L-cysteine; PARP1: poly(ADP-ribose) polymerase 1; RAP2A: member of RAS oncogene family; RHEB: Ras homolog enriched in brain; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; RRAGB: Ras related GTP binding B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TRIM37: tripartite motif containing 37.
TRIM37 基因突变导致肌肉-肝脏-大脑-眼睛矮小症（mulibrey），一种产前发病的严重生长障碍。尽管 TRIM37 缺失通常会诱导细胞凋亡，但携带 TRIM37 突变的患者患肿瘤的风险很高，这表明 TRIM37 缺陷肿瘤细胞可能存在另一种存活机制。我们发现 TRIM37 与 MTOR 和 RRAGB 蛋白相互作用，增强了 MTOR-RRAGB 相互作用，并促进了 MTOR 的溶酶体定位，从而激活了氨基酸刺激的 MTORC1 信号通路。在 TRIM37 功能丧失的情况下，TFEB 的磷酸化显著减少，导致其转位到细胞核，使其能够转录激活参与溶酶体生物发生和巨自噬/自噬的基因。增强的自噬依赖于 MTORC1 信号的抑制，可能是 TRIM37 功能丧失后存活的替代机制。我们的研究揭示了 TRIM37 在调节 MTORC1-TFEB 轴中的积极作用，并为肌肉-肝脏-大脑-眼睛矮小症的发病机制以及潜在的治疗方法提供了机制见解。
ACTB：肌动蛋白 beta；ATG：自噬相关；CASP3：半胱氨酸天冬氨酸蛋白酶 3；CLEAR：协调溶酶体表达和调节；CQ：氯喹；CTS：组织蛋白酶蛋白酶；CTSL：组织蛋白酶 L；EIF4EBP1：真核翻译起始因子 4E 结合蛋白 1；LAMP1：溶酶体相关膜蛋白 1；LAMP2：溶酶体相关膜蛋白 2；LMNB1：核纤层蛋白 B1；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3B；MTOR：雷帕霉素靶蛋白激酶；MTORC1：MTOR 复合物 1；mulibrey：肌肉-肝脏-大脑-眼睛；NAC：N-乙酰-L-半胱氨酸；PARP1：多聚（ADP-核糖）聚合酶 1；RAP2A：RAS 癌基因家族成员；RHEB：脑丰富的 Ras 同源物；ROS：活性氧；RPS6KB1：核糖体蛋白 S6 激酶 B1；RRAGB：Ras 相关 GTP 结合 B；SQSTM1：自噬体 1；TFEB：转录因子 EB；TRIM37：含三部分基序 37。
