核信号通路 ERBB4
中文名称
通路描述
除了作为跨膜受体信号传导外，ERBB4 JM-A 等位基因（ERBB4 JM-A CYT1 和 ERBB4 JM-A CYT2）的配体激活的同源二聚体在局灶膜区被 ADAM17（TACE）蛋白酶切割，导致胞外区脱落并形成 80 kDa 的膜结合 ERBB4 片段，称为 ERBB4 m80（Rio et al. 2000, Cheng et al. 2003）。ERBB4 m80 进一步被 gamma 分泌酶复合物介导的蛋白酶切割，释放出可溶性 80 kDa ERBB4 胞内区，称为 ERBB4 s80 或 E4ICD，进入细胞质（Ni et al. 2001）。ERBB4 s80 可转运至细胞核，促进多种转录因子的核转运，并作为转录共激活因子发挥作用。在神经前体细胞中，ERBB4 s80 结合 TAB 和 NCOR1 复合物，帮助其进入细胞核，并作为 TAB:NCOR1 介导的抑制星形胶质细胞分化基因 GFAP 和 S100B 表达的共激活因子（Sardi et al. 2006）。在乳腺细胞中，ERBB4 s80 招募细胞质中的 STAT5A 转录因子，将其转运至细胞核，并在结合和促进 beta-casein（CSN2）启动子转录中作为 STAT5A 共激活因子发挥作用，可能还参与调节其他与泌乳相关的基因（Williams et al. 2004, Muraoka-Cook et al. 2008）。ERBB4 s80 还被证明在细胞核中与激活的雌激素受体结合，作为其转录共激活因子，促进一些雌激素调节基因（如孕激素受体基因 NR3C3 和 CXCL12 即 SDF1）的转录（Zhu et al. 2006）。ERBB4s80 可能通过增加 TERT 基因启动子的甲基化来抑制转录逆转录酶（TERT）的转录（Ishibashi et al. 2012）。ERBB4 的 C 尾具有几个 WW 结构域结合基序（CYT1 等位基因中有三个，CYT2 等位基因中有两个），使 ERBB4 能与 WW 结构域结合蛋白相互作用。ERBB4 s80 通过 WW 结构域结合基序与 YAP1 转录因子相互作用，YAP1 是一种已知的原癌基因，ERBB4 s80 可能是 YAP1 介导转录的共调节因子（Komuro et al. 2003, Omerovic et al. 2004）。肿瘤抑制蛋白 WWOX 是另一个 WW 结构域结合蛋白，它与 YAP1 竞争结合 ERBB4 s80，并阻止 ERBB4 s80 的核转运（Aqeilan et al. 2005）。ERBB4 s80 也能转运至线粒体基质，这似乎是在其核转运被抑制时发生的。一旦进入线粒体，ERBB4 的 BH3 结构域，作为 BCL2 家族成员的特征，可能使其成为促凋亡因子（Naresh et al. 2006）。
英文描述
Mitochondrial RNA degradation The human mitochondrial genome encodes two rRNAs, 22 tRNAs, and 13 proteins. The mitochondrial genome is transcribed from two divergent promoters into two large precursor RNAs, one from each strand, that are endonucleolytically processed into individual mRNAs, tRNAs, and rRNAs (Mercer et al. 2011, reviewed in Barchiesi and Vascotto 2019, Jedynak-Slyvka et al. 2021, Rackham and Filipovska 2022). Heavy strand (H-strand) DNA is significantly more G-rich than light strand (L-strand) DNA. Transcripts from the H-strand encode eight monocistronic mRNAs, two bicistronic mRNAs (MT-ATP8/6 and MT-ND4L/4), 14 tRNAs, and two rRNAs. Transcripts from the Lâstrand encode only one mRNA (MTâND6), one long non-coding RNA (lncRNA), lncND6, which is antisense to MT-ND6, and eight tRNAs, and two long non-coding RNAs designated as lncND5, and lncCyt b RNA that are antisense to the coding mRNAs MT-ND5 and MT-CYB (CYTB, MT-Cytb) (Rackham et al. 2011). The L-strand and H-strand transcripts are complementary and, therefore, have the potential to form large double-stranded RNAs (dsRNAs), yet very little dsRNA is observed in wild-type mitochondria.
Both dsRNAs and normal mRNAs, tRNAs, and rRNAs are hydrolyzed by the SUPV3L1:PNPT1 complex, called the degradosome, which is located mostly in mitochondrial RNA granules (MRGs) adjacent to the DNA-containing nucleoid (reviewed in Borowski et al. 2010, Rorbach and Minczuk 2012, Kotrys and Szczesny 2019, Rackham and Filipovska 2022). Degradation appears to occur in subregions of MRGs called D-foci (Borowski et al. 2013, Van Haute et al. 2015). SUPV3L1 is a helicase that unwinds double-stranded RNA (Shu et al. 2004, Wang et al. 2009, Dhir et al. 2018, Jain et al. 2022) to provide single-stranded substrate to the PNPT1 exonuclease (Wang et al. 2009, Lin et al. 2012). Additionally, G quadruplex structures in a subset of RNAs are unwound by GRSF1 to provide substrates to the SUPV3L1:PNPT1 complex (Antonicka et al. 2013, Pietras et al. 2018). However, other RNAs are stabilized by GRSF1 (Antonicka et al. 2013). The PNPT1 3'-5' exonuclease hydrolyzes RNAs to yield 4-5 nucleotide "nanoRNAs" which are further hydrolyzed to mononucleotides by the REXO2 dimer (Bruni et al. 2013, Szewczyk et al. 2020).
Degradation of mitochondrial RNAs is regulated by RNA-binding proteins: FASTK, FASTKD1-5, and the SLIRP:LRPPRC complex (Sasarman et al. 2010, Chujo et al. 2021, Ruzzenente et al. 2012, Jourdain et al. 2017, Siira et al. 2017, reviewed in Rackham and Filipovska 2022). SLIRP:LRPPRC binds throughout the mitochondrial transcriptome, including 12S rRNA, 16S rRNA, and 13 mRNAs, and acts to stabilize RNA structures, inhibit hybridization of complementary RNAs, and extend the half-lives of RNAs (Sasarman et al. 2010, Chujo et al. 2012, Siira et al. 2017). Fas-activated serine/threonine kinase (FASTK) and its homologs FASTKD1-5 bind particular mitochondrial RNAs and affect their stability and processing (reviewed in Jourdain et al. 2017, Rackham and Filipovska 2022).
Both dsRNAs and normal mRNAs, tRNAs, and rRNAs are hydrolyzed by the SUPV3L1:PNPT1 complex, called the degradosome, which is located mostly in mitochondrial RNA granules (MRGs) adjacent to the DNA-containing nucleoid (reviewed in Borowski et al. 2010, Rorbach and Minczuk 2012, Kotrys and Szczesny 2019, Rackham and Filipovska 2022). Degradation appears to occur in subregions of MRGs called D-foci (Borowski et al. 2013, Van Haute et al. 2015). SUPV3L1 is a helicase that unwinds double-stranded RNA (Shu et al. 2004, Wang et al. 2009, Dhir et al. 2018, Jain et al. 2022) to provide single-stranded substrate to the PNPT1 exonuclease (Wang et al. 2009, Lin et al. 2012). Additionally, G quadruplex structures in a subset of RNAs are unwound by GRSF1 to provide substrates to the SUPV3L1:PNPT1 complex (Antonicka et al. 2013, Pietras et al. 2018). However, other RNAs are stabilized by GRSF1 (Antonicka et al. 2013). The PNPT1 3'-5' exonuclease hydrolyzes RNAs to yield 4-5 nucleotide "nanoRNAs" which are further hydrolyzed to mononucleotides by the REXO2 dimer (Bruni et al. 2013, Szewczyk et al. 2020).
Degradation of mitochondrial RNAs is regulated by RNA-binding proteins: FASTK, FASTKD1-5, and the SLIRP:LRPPRC complex (Sasarman et al. 2010, Chujo et al. 2021, Ruzzenente et al. 2012, Jourdain et al. 2017, Siira et al. 2017, reviewed in Rackham and Filipovska 2022). SLIRP:LRPPRC binds throughout the mitochondrial transcriptome, including 12S rRNA, 16S rRNA, and 13 mRNAs, and acts to stabilize RNA structures, inhibit hybridization of complementary RNAs, and extend the half-lives of RNAs (Sasarman et al. 2010, Chujo et al. 2012, Siira et al. 2017). Fas-activated serine/threonine kinase (FASTK) and its homologs FASTKD1-5 bind particular mitochondrial RNAs and affect their stability and processing (reviewed in Jourdain et al. 2017, Rackham and Filipovska 2022).
所含基因
6 个基因