YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization
YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization
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YWHA/14-3-3 蛋白通过非规范模式识别磷酸化 TFEB，以控制 TFEB 细胞质定位
DOI：
10.1080/15548627.2019.1569928
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发表时间：
2019-01
期刊：
影响因子：
13.3
通讯作者：
Feng Wei
中科院分区：
文献类型：
--
作者：
Xu Yang;Ren Jinqi;He Xiaolong;Chen Han;Wei Taotao;Feng Wei
摘要转录因子EB（TFEB）作为巨自噬/自噬-溶酶体途径的主要调节因子，在神经退行性疾病和癌症的调控中发挥着重要作用。TFEB的转录活性受到磷酸化和去磷酸化的严格控制。TFEB的磷酸化S211（p-S211）可以被YWHA/14-3-3蛋白识别用于TFEB的胞质定位。在这里，我们表征了磷酸化TFEB和YWHA/14-3-3蛋白之间的相互作用，并确定了与TFEB p-S211-肽复合的YWHA/14-3-3蛋白的结构。虽然在TFEB p-S211-肽的N末端缺失了YWHA/14-3-3识别的关键精氨酸，但肽的C末端额外疏水残基意外地占据了YWHA/14-3-3蛋白的靶结合沟的近一半，这补偿了N末端缺陷，并且与典型的YWHA/14-3-3-结合模式不同。TFEB与YWHA/14-3-3蛋白相互作用界面的必需残基突变破坏了它们的相互作用，严重损害了TFEB的细胞质定位，从而改变了TFEB靶基因的表达，影响了自噬。因此，YWHA/14-3-3蛋白识别磷酸化TFEB的非典型模式控制TFEB的细胞质定位和其活性。简称：ACTB：肌动蛋白β; ALP：自噬-溶酶体途径; ATP6V1H：ATP酶H+转运V1亚基H; bHLH：碱性螺旋-环-螺旋; CLEAR：协调的溶酶体表达和调节; Co-IP：免疫共沉淀; CTSB：组织蛋白酶B; CTSD：组织蛋白酶D; LAM 1：溶酶体相关膜蛋白1; MAP 1 LC 3/LC 3：微管相关蛋白1轻链3; MITF：黑素细胞诱导转录因子; NLS：核定位信号; TFE B：转录因子EB; YWHA/14-3-3：酪氨酸3-单加氧酶/色氨酸5-单加氧酶激活蛋白。
ABSTRACT As a master regulator of the macroautophagy/autophagy-lysosomal pathway, TFEB (transcription factor EB) plays a prominent role in regulating neurodegenerative diseases and cancer. The transcription activity of TFEB is tightly controlled by phosphorylation and dephosphorylation. Phosphorylated S211 (p-S211) of TFEB can be recognized by YWHA/14-3-3 proteins for TFEB cytoplasmic localization. Here, we characterized the interactions between phosphorylated TFEB and YWHA/14-3-3 proteins and determined the structures of YWHA/14-3-3 proteins in complex with a TFEB p-S211-peptide. Although the critical arginine for YWHA/14-3-3 recognition is missing in the N terminus of the TFEB p-S211-peptide, the C-terminal additional hydrophobic residues of the peptide unexpectedly occupy nearly half of the target-binding groove of YWHA/14-3-3 proteins, which compensates for the N-terminal defect and is distinct from the canonical YWHA/14-3-3-binding mode. Mutations of essential residues in the interaction interface between TFEB and YWHA/14-3-3 proteins disrupted their interactions and severely impaired the cytoplasmic localization of TFEB, which altered the expression of TFEB target genes and affected autophagy. Thus, YWHA/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization and its activity. Abbreviation: ACTB: actin beta; ALP: autophagy-lysosomal pathway; ATP6V1H: ATPase H+ transporting V1 subunit H; bHLH: basic helix-loop-helix; CLEAR: coordinated lysosomal expression and regulation; Co-IP: co-immunoprecipitation; CTSB: cathepsin B; CTSD: cathepsin D; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MITF: melanocyte inducing transcription factor; NLS: nuclear localization signal; TFEB: transcription factor EB; YWHA/14-3-3: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein.
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影响因子：
14.8
作者：
Gietz, R. Daniel;Schiestl, Robert H.
通讯作者：
Schiestl, Robert H.
影响因子：
21.3
作者：
Medina DL;Di Paola S;Peluso I;Armani A;De Stefani D;Venditti R;Montefusco S;Scotto-Rosato A;Prezioso C;Forrester A;Settembre C;Wang W;Gao Q;Xu H;Sandri M;Rizzuto R;De Matteis MA;Ballabio A
通讯作者：
Ballabio A
DOI：
10.1083/jcb.200909067
发表时间：
2009-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Thompson LM;Aiken CT;Kaltenbach LS;Agrawal N;Illes K;Khoshnan A;Martinez-Vincente M;Arrasate M;O'Rourke JG;Khashwji H;Lukacsovich T;Zhu YZ;Lau AL;Massey A;Hayden MR;Zeitlin SO;Finkbeiner S;Green KN;LaFerla FM;Bates G;Huang L;Patterson PH;Lo DC;Cuervo AM;Marsh JL;Steffan JS
通讯作者：
Steffan JS
影响因子：
17.1
作者：
Tsunemi T;Ashe TD;Morrison BE;Soriano KR;Au J;Roque RA;Lazarowski ER;Damian VA;Masliah E;La Spada AR
通讯作者：
La Spada AR
影响因子：
11.4
作者：
Pena-Llopis, Samuel;Vega-Rubin-de-Celis, Silvia;Schwartz, Jacob C.;Wolff, Nicholas C.;Tran, Tram Anh T.;Zou, Lihua;Xie, Xian-Jin;Corey, David R.;Brugarolas, James
通讯作者：
Brugarolas, James