Journal of Biological Chemistry最新文献_第2页

GRK5 regulates endocytosis of FPR2 independent of β-Arrestins.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108112

Christine E Jack, Emily M Cope, Laura Lemel, Meritxell Canals, Julia Drube, Carsten Hoffmann, Asuka Inoue, James N Hislop, Dawn Thompson

{"title":"GRK5 regulates endocytosis of FPR2 independent of β-Arrestins.","authors":"Christine E Jack, Emily M Cope, Laura Lemel, Meritxell Canals, Julia Drube, Carsten Hoffmann, Asuka Inoue, James N Hislop, Dawn Thompson","doi":"10.1016/j.jbc.2024.108112","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108112","url":null,"abstract":"The formyl-peptide receptor 2 (FPR2) is a G-protein-coupled receptor (GPCR) that responds to pathogen-derived peptides and regulates both pro-inflammatory and pro-resolution cellular processes. While ligand selectivity and G-protein-signalling of FPR2 have been well characterized, molecular mechanisms controlling subsequent events such as endocytosis and recycling to the plasma membrane are less understood. Here we show the key role of the GPCR kinase 5 (GRK5) in facilitating FPR2 endocytosis and post-endocytic trafficking. We found, in response to activation by a synthetic peptide WKYMVm, the recruitment of β-Arrestins to the receptor requires both putative phosphorylation sites in the C-terminal of FPR2 and the presence of GRKs, predominantly GRK5. Furthermore, although GRKs are required for β-Arrestin recruitment and endocytosis, the recruitment of β-Arrestin is not itself essential for FPR2 endocytosis. Instead, β-Arrestin determines post-endocytic delivery of FPR2 to subcellular compartments and subsequent plasma membrane delivery and controls the magnitude of downstream signal transduction. Collectively, the newly characterized FPR2 molecular pharmacology will facilitate the design of more efficient therapeutics targeting chronic inflammation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108112"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Missense Mutations of the Ephrin Receptor EPHA1 Associated with Alzheimer's Disease Disrupt Receptor Signaling Functions.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108099

Mike Matsumoto, Maricel Gomez-Soler, Sara Lombardi, Bernhard C Lechtenberg, Elena B Pasquale

{"title":"Missense Mutations of the Ephrin Receptor EPHA1 Associated with Alzheimer's Disease Disrupt Receptor Signaling Functions.","authors":"Mike Matsumoto, Maricel Gomez-Soler, Sara Lombardi, Bernhard C Lechtenberg, Elena B Pasquale","doi":"10.1016/j.jbc.2024.108099","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108099","url":null,"abstract":"Missense mutations in the EPHA1 receptor tyrosine kinase have been identified in Alzheimer's patients. To gain insight into their potential role in disease pathogenesis, we investigated the effects of four of these mutations. We show that the P460L mutation in the second fibronectin type III (FN2) domain drastically reduces EPHA1 cell surface localization while increasing tyrosine phosphorylation of the cell surface localized receptor. The R791H mutation in the kinase domain abolishes EPHA1 tyrosine phosphorylation, indicating abrogation of kinase-dependent signaling. Furthermore, both mutations decrease EPHA1 phosphorylation on S906 in the kinase-SAM linker region, suggesting impairment of a non-canonical form of signaling regulated by serine/threonine kinases. The R492Q mutation, also in the FN2 domain, has milder effects than the P460L mutation while the R926C mutation in the SAM domain increases S906 phosphorylation. We also found that EPHA1 undergoes constitutive proteolytic cleavage in the FN2 domain, generating a soluble 55 kDa N-terminal fragment containing the ligand-binding domain and a transmembrane 60 kDa C-terminal fragment. The 60 kDa wild-type fragment is phosphorylated on both tyrosine residues and S906, suggesting signaling functions. The P460L mutant 60 kDa fragment undergoes proteasomal degradation and the R791H mutant fragment lacks tyrosine phosphorylation and has decreased S906 phosphorylation. These findings advance our understanding of EPHA1 signaling mechanisms and support the notion that alterations in EPHA1 signaling due to missense mutations contribute to Alzheimer's disease pathogenesis.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108099"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The C-terminal α-helix is crucial for the activity of the bacterial ABC transporter BmrA.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108098

Veronika Osten, Kristin Oepen, Dirk Schneider

{"title":"The C-terminal α-helix is crucial for the activity of the bacterial ABC transporter BmrA.","authors":"Veronika Osten, Kristin Oepen, Dirk Schneider","doi":"10.1016/j.jbc.2024.108098","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108098","url":null,"abstract":"ABC transporters are membrane integral proteins that consist of a transmembrane (TMD) and nucleotide-binding domain (NBD). Two monomers (half-transporters) of the Bacillus subtilis ABC transporter BmrA (Bacillus multidrug-resistance ATP) dimerize to build a functional full-transporter. As all ABC exporters, BmrA uses the free energy of ATP hydrolysis to transport substrate molecules across the cell membrane. For substrate transport, a BmrA dimer undergoes major conformational changes. ATP binding drives dimerization of the NBDs followed by the hydrolysis of the nucleotides. Conserved structural elements within the NBD and TMD are crucial for dimerization and the activity of BmrA. In the BmrA structure, an α-helix is present at the C-terminus, which can be subdivided in two smaller helices. As shown here, the very C-terminal helix (fragment) is not crucial for the BmrA activity. In fact, based on Cys-scanning mutagenesis, this region is highly flexible. In contrast, a BmrA variant lacking the entire C-terminal α-helix, showed no ATPase and transport activity. Via Ala-scanning we identified residues in the N-terminal fragment of the helix that are crucial for the BmrA activity, most likely via establishing contacts to structural elements involved in ATP recognition, binding and/or hydrolysis.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108098"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A PDZ-kinase allosteric relay mediates Par complex regulator exchange.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108097

Elizabeth Vargas, Rhiannon R Penkert, Kenneth E Prehoda

{"title":"A PDZ-kinase allosteric relay mediates Par complex regulator exchange.","authors":"Elizabeth Vargas, Rhiannon R Penkert, Kenneth E Prehoda","doi":"10.1016/j.jbc.2024.108097","DOIUrl":"10.1016/j.jbc.2024.108097","url":null,"abstract":"The Par complex polarizes the plasma membrane of diverse animal cells using the catalytic activity of atypical Protein Kinase C (aPKC) to pattern substrates. Two upstream regulators of the Par complex, Cdc42 and Par-3, bind separately to the complex to influence its activity in different ways. Each regulator binds a distinct member of the complex, Cdc42 to Par-6 and Par-3 to aPKC, making it unclear how they influence one another's binding. Here we report the discovery that Par-3 binding to aPKC is regulated by aPKC autoinhibition and link this regulation to Cdc42 and Par-3 exchange. The Par-6 PDZ domain activates aPKC binding to Par-3 via a novel interaction with the aPKC kinase domain. Cdc42 and Par-3 have opposite effects on the Par-6 PDZ-aPKC kinase interaction: while the Par-6 kinase domain interaction competes with Cdc42 binding to the complex, Par-3 binding is enhanced by the interaction. The differential effect of Par-3 and Cdc42 on the Par-6 PDZ interaction with the aPKC kinase domain forms an allosteric relay that connects their binding sites and is responsible for the negative cooperativity that underlies Par complex polarization and activity.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108097"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bending stiffness of Toxoplasma gondii actin filaments.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108101

Wenxiang Cao, Thomas E Sladewski, Aoife T Heaslip, Enrique M De La Cruz

{"title":"Bending stiffness of Toxoplasma gondii actin filaments.","authors":"Wenxiang Cao, Thomas E Sladewski, Aoife T Heaslip, Enrique M De La Cruz","doi":"10.1016/j.jbc.2024.108101","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108101","url":null,"abstract":"Actin is essential for the survival and pathogenicity of the Apicomplexan parasite Toxoplasma gondii, where it plays essential functions in cargo transport, invasion, egress, and organelle inheritance. Recent work has shown that, unlike vertebrate skeletal muscle actin, purified T. gondii actin filaments (TgAct1) can undergo rapid treadmilling, due to large differences in the barbed- and pointed-end critical concentrations, rapid subunit dissociation from filament ends, and a rapid nucleotide exchange rate constant from free monomers. Previous structural analysis suggested that the unique assembly properties of TgAct1filaments may be a functional consequence of reduced contacts between the DNAse-1 binding loop (D-loop) of a filament subunit and its adjacent, long-axis subunit neighbor. Because the D-loop makes stabilizing interactions between neighboring subunits, it has been implicated in regulating the mechanical properties of actin filaments. In this study, we measured the bending persistence length (LB) of TgAct1 filaments and the filament length distribution. We found that despite compromised intersubunit D-loop contacts, TgAct1 filaments have similar bending stiffness and thermodynamic stability as vertebrate actin filaments. Analysis of published cryoEM image density maps indicates that TgAct1 filaments retain a stabilizing inter-subunit salt bridge between E168 and K62 and reveals visible density between Y167 and S61 of adjacent filament subunits, consistent with a conserved cation binding site proximal to the D-loop, as initially identified in vertebrate skeletal muscle actin filaments. These results favor a mechanism in which weak D-loop interactions compromise TgAct1 subunit incorporation at filament ends, while minimally affecting overall subunit interactions within filaments.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108101"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

One-for-all gene inactivation via PAM-independent base editing in bacteria.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108113

Xin Li, Ying Wei, Shu-Yan Wang, Shu-Guang Wang, Peng-Fei Xia

{"title":"One-for-all gene inactivation via PAM-independent base editing in bacteria.","authors":"Xin Li, Ying Wei, Shu-Yan Wang, Shu-Guang Wang, Peng-Fei Xia","doi":"10.1016/j.jbc.2024.108113","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108113","url":null,"abstract":"Base editing is preferable for bacterial gene inactivation without generating double strand breaks, requiring homology recombination or highly efficient DNA delivery capability. However, the potential of base editing is limited by the adjoined dependence on the editing window and protospacer adjacent motif (PAM). Herein, we report an unconstrained base editing system to enable the inactivation of any genes of interest (GOIs) in bacteria. We employed a dCas9 derivative, dSpRY, and activation-induced cytidine deaminase to build a PAM-independent base editor. Then, we programmed the base editor to exclude the START codon of a GOI instead of introducing premature STOP codons to obtain a universal approach for gene inactivation, namely XSTART, with an overall efficiency approaching 100%. By using XSTART, we successfully manipulated the amino acid metabolisms in Escherichia coli, generating glutamine, arginine, and aspartate auxotrophic strains. While we observed a high frequency of off-target events as a trade-off for increased efficiency, refining the regulatory system of XSTART to limit expression levels reduced off-target events by over 60% without sacrificing efficiency, aligning our results with previously reported levels. Finally, the effectiveness of XSTART was also demonstrated in probiotic E. coli Nissle 1917 and photoautotrophic cyanobacterium Synechococcus elongatus, illustrating its potential in reprogramming diverse bacteria.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108113"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Magnesium-dependent-Protein Phosphatase 1B Regulates the Protein Arginine Methyltransferase 5 Through the Modulation of Myosin Phosphatase.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108107

Ilka Keller, Ádám Ungvári, Evelin Major, Dániel Horváth, Zoltán Kónya, Emese Tóth, Ferenc Erdődi, Andrea Kiss, Beáta Lontay

{"title":"Magnesium-dependent-Protein Phosphatase 1B Regulates the Protein Arginine Methyltransferase 5 Through the Modulation of Myosin Phosphatase.","authors":"Ilka Keller, Ádám Ungvári, Evelin Major, Dániel Horváth, Zoltán Kónya, Emese Tóth, Ferenc Erdődi, Andrea Kiss, Beáta Lontay","doi":"10.1016/j.jbc.2024.108107","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108107","url":null,"abstract":"Dysregulation of the expression levels and the activity of kinases/phosphatases is an intrinsic hallmark of tumor transformation and progression, as either as a primary cause or consequence. The myosin phosphatase (MP)/protein arginine methyltransferase 5 (PRMT5)/histone (H4) pathway is an oncogenic signaling pathway downregulating the gene expression of tumor suppressors. However, the upstream regulators of the pathway are unknown. We show that the Mg2+-dependent protein phosphatase 1 B (PP2Cb or PPM1B) interacts and regulates MP through the MYPT1 regulatory subunit, and this interplay results in the inactivation of the tumorigenic pathway driven by PRMT5. The phospho-Thr696 inhibitory residues of the MYPT1 regulatory subunit of MP was dephosphorylated by PPM1B. The inhibition of PPM1B by sanguinarine (SNG) resulted in the deactivation of MP and the increased activity of PRMT5 leading to increased symmetric dimethylation of histone H4 in HeLa cells. The overexpression of the PPM1B had the opposite action. The overexpression of PPM1B decreased the colonization activity of HeLa cells through modulation of MP. Finally, human cervical carcinoma biopsies showed almost complete elimination of PPM1B compared to their healthy control counterparts. The phosphorylation of the inhibitory MYPT1pT696 and the regulatory PRMT5pT80 residues and the symmetric dimethylation of H4 were elevated in the cancer biopsies and it resulted in a decrease in retinoblastoma protein expression. The results indicate a tumor suppressor role of the PPM1B/MP axis via inhibition of PRMT5, thereby regulating gene expression through H4 arginine dimethylation. Collectively, PPM1B is a tumor suppressor and a possible tumor marker for cervical carcinoma.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108107"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PRDX4 mitigates diabetic retinopathy by inhibiting reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108111

Yue Huang, Yuting Zhang, Yuan Liu, Yinan Jin, Hongwei Yang

{"title":"PRDX4 mitigates diabetic retinopathy by inhibiting reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells.","authors":"Yue Huang, Yuting Zhang, Yuan Liu, Yinan Jin, Hongwei Yang","doi":"10.1016/j.jbc.2024.108111","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108111","url":null,"abstract":"Diabetic retinopathy (DR) is a neurovascular complication of diabetes. As a crucial player in the retinal physiology, Müller cells are affected in DR, impairments of Müller cell function lead to retinal malfunctions. Therefore, searching for approaches to mitigate diabetes-induced injury in Müller cells is imperative for delaying DR. Peroxiredoxin 4 (PRDX4), an important endoplasmic reticulum (ER)-resident antioxidant, was explored in this study for its potential protective role against DR. Streptozotocin (STZ)-induced mouse model of diabetes and high glucose (HG)-induced Müller cells were utilized to assess the impact of PRDX4. Compared to wild-type mice, PRDX4 knockout exacerbated retinal neurodegeneration, reactive gliosis, cell apoptosis, endoplasmic reticulum (ER) stress, oxidative stress, and mitochondrial dysfunction in diabetic retinas. Knockdown of PRDX4 aggravated high glucose (HG)-induced reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells. Conversely, PRDX4 overexpression in Müller cells protected against HG-induced cell damage. Mechanistically, PRDX4 promoted the degradation of DPP4, which is associated with DR in type 1 diabetics, thereby alleviating HG-stimulated Müller cell abnormalities. Our study indicated that PRDX4 is a crucial protective regulator in DR progression via destabilization of DPP4 protein and suggested enhancement of PRDX4 level may represent a promising approach for treating DR.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108111"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hyperactivation of human acidic chitinase (Chia) for potential medical use.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108100

Kazuaki Okawa, Masashi Kijima, Mana Ishii, Maeda Nanako, Yudai Yasumura, Masayoshi Sakaguchi, Masahiro Kimura, Maiko Uehara, Eri Tabata, Peter O Bauer, Fumitaka Oyama

{"title":"Hyperactivation of human acidic chitinase (Chia) for potential medical use.","authors":"Kazuaki Okawa, Masashi Kijima, Mana Ishii, Maeda Nanako, Yudai Yasumura, Masayoshi Sakaguchi, Masahiro Kimura, Maiko Uehara, Eri Tabata, Peter O Bauer, Fumitaka Oyama","doi":"10.1016/j.jbc.2024.108100","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108100","url":null,"abstract":"Accumulation of environmental chitin in the lungs can lead to pulmonary fibrosis, characterized by inflammatory infiltration and fibrosis in acidic chitinase (Chia)-deficient mice. Transgenic expression of Chia in these mice ameliorated the symptoms, indicating the potential of enzyme supplementation as a promising therapeutic strategy for related lung diseases. This study focuses on utilizing hyperactivated human Chia, which exhibits low activity. We achieved significant activation of human Chia by incorporating nine amino acids derived from the crab-eating monkey (Macaca fascicularis) Chia, known for its robust chitin-degrading activity. The modified human Chia retained high activity across a broad pH spectrum and exhibited enhanced thermal stability. The amino acid substitutions associated with hyperactivation of human Chia activity occurred species-specifically in monkey Chia. This discovery highlights the potential of hyperactivated Chia in treating pulmonary diseases resulting from chitin accumulation in human lungs.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108100"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The steroid hormone 20-hydroxyecdysone inhibits RAPTOR expression by repressing Hox gene transcription to induce autophagy.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-18 DOI: 10.1016/j.jbc.2024.108093

Tianwen Liu, Can Tian, Yanxue Li, Jinxing Wang, Xiaofan Zhao

{"title":"The steroid hormone 20-hydroxyecdysone inhibits RAPTOR expression by repressing Hox gene transcription to induce autophagy.","authors":"Tianwen Liu, Can Tian, Yanxue Li, Jinxing Wang, Xiaofan Zhao","doi":"10.1016/j.jbc.2024.108093","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108093","url":null,"abstract":"Regulatory-associated protein of TOR (RAPTOR) is a key component of TOR complex 1 (TORC1), which determines the lysosomal location and substrate recruitment of TORC1 to promote cell growth and prevent autophagy. Many studies in recent decades have focused on the posttranslational modification of RAPTOR; however, little is known about the transcriptional regulatory mechanism of Raptor. Using the lepidopteran insect cotton bollworm (Helicoverpa armigera) as model, we reveal the transcriptional regulatory mechanism of Raptor. RAPTOR has different expression profiles in tissues during development from larva to late pupa, with high expression levels at larval feeding stages but low expression levels during metamorphic stages in the epidermis, midgut and fat body. RAPTOR is localized in the larval midgut at the feeding stage but is localized in the imaginal midgut at metamorphic stages. The knockdown of Raptor at the feeding stage results in the production of small pupae, early autophagy of the midgut and fat body, and decreased cell proliferation. However, Raptor knockdown at metamorphic stage represses the development of the epidermis, adult fat body and brain. 20-Hydroxecdysone (20E) represses Raptor transcription. Homeobox (HOX) proteins promote Raptor transcription by binding to its promoter. Overexpression of HOX proteins represses ATG expression and autophagy but increases cell proliferation. 20E represses Hox genes transcription via its nuclear receptor EcR binding to its promoters. Together, these findings suggest that HOX proteins are positive regulators that upregulate Raptor transcription. 20E represses Hox gene transcription, thus repressing Raptor expression, resulting in autophagy and repressing cell proliferation during metamorphosis.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108093"},"PeriodicalIF":4.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0