Biochemical Journal最新文献_第7页

Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7. 激活素 E 是一种 TGFβ 配体，可通过激活素受体样激酶 7 发出特异性信号。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/BCJ20230404

Kylie A Vestal, Chandramohan Kattamuri, Muhasin Koyiloth, Luisina Ongaro, James A Howard, Aimee M Deaton, Simina Ticau, Aditi Dubey, Daniel J Bernard, Thomas B Thompson

{"title":"Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7.","authors":"Kylie A Vestal, Chandramohan Kattamuri, Muhasin Koyiloth, Luisina Ongaro, James A Howard, Aimee M Deaton, Simina Ticau, Aditi Dubey, Daniel J Bernard, Thomas B Thompson","doi":"10.1042/BCJ20230404","DOIUrl":"10.1042/BCJ20230404","url":null,"abstract":"Activins are one of the three distinct subclasses within the greater Transforming growth factor β (TGFβ) superfamily. First discovered for their critical roles in reproductive biology, activins have since been shown to alter cellular differentiation and proliferation. At present, members of the activin subclass include activin A (ActA), ActB, ActC, ActE, and the more distant members myostatin and GDF11. While the biological roles and signaling mechanisms of most activins class members have been well-studied, the signaling potential of ActE has remained largely unknown. Here, we characterized the signaling capacity of homodimeric ActE. Molecular modeling of the ligand:receptor complexes showed that ActC and ActE shared high similarity in both the type I and type II receptor binding epitopes. ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. In mature murine adipocytes, ActE invoked a SMAD2/3 response via ALK7, like ActC. Collectively, our results establish ActE as a specific signaling ligand which activates the type I receptor, ALK7.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"547-564"},"PeriodicalIF":4.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability DoUBLing起来：泛素和泛素样蛋白酶在基因组稳定性中的作用

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-04-10 DOI: 10.1042/bcj20230284

Foster, Benjamin M., Wang, Zijuan, Schmidt, Christine K.

{"title":"DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability","authors":"Foster, Benjamin M., Wang, Zijuan, Schmidt, Christine K.","doi":"10.1042/bcj20230284","DOIUrl":"https://doi.org/10.1042/bcj20230284","url":null,"abstract":"Maintaining stability of the genome requires dedicated DNA repair and signalling processes that are essential for the faithful duplication and propagation of chromosomes. These DNA damage response (DDR) mechanisms counteract the potentially mutagenic impact of daily genotoxic stresses from both exogenous and endogenous sources. Inherent to these DNA repair pathways is the activity of protein factors that instigate repair processes in response to DNA lesions. The regulation, coordination, and orchestration of these DDR factors is carried out, in a large part, by post-translational modifications, such as phosphorylation, ubiquitylation, and modification with ubiquitin-like proteins (UBLs). The importance of ubiquitylation and UBLylation with SUMO in DNA repair is well established, with the modified targets and downstream signalling consequences relatively well characterised. However, the role of dedicated erasers for ubiquitin and UBLs, known as deubiquitylases (DUBs) and ubiquitin-like proteases (ULPs) respectively, in genome stability is less well established, particularly for emerging UBLs such as ISG15 and UFM1. In this review, we provide an overview of the known regulatory roles and mechanisms of DUBs and ULPs involved in genome stability pathways. Expanding our understanding of the molecular agents and mechanisms underlying the removal of ubiquitin and UBL modifications will be fundamental for progressing our knowledge of the DDR and likely provide new therapeutic avenues for relevant human diseases, such as cancer.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"13 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140346240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases. 共济失调蛋白-3的去泛素化酶功能及其在马查多-约瑟夫病和其他疾病的发病机制中的作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-20 DOI: 10.1042/BCJ20240017

Anastasiya Potapenko, Jennilee M Davidson, Albert Lee, Angela S Laird

{"title":"The deubiquitinase function of ataxin-3 and its role in the pathogenesis of Machado-Joseph disease and other diseases.","authors":"Anastasiya Potapenko, Jennilee M Davidson, Albert Lee, Angela S Laird","doi":"10.1042/BCJ20240017","DOIUrl":"10.1042/BCJ20240017","url":null,"abstract":"Machado-Joseph disease (MJD) is a devastating and incurable neurodegenerative disease characterised by progressive ataxia, difficulty speaking and swallowing. Consequently, affected individuals ultimately become wheelchair dependent, require constant care, and face a shortened life expectancy. The monogenic cause of MJD is expansion of a trinucleotide (CAG) repeat region within the ATXN3 gene, which results in polyglutamine (polyQ) expansion within the resultant ataxin-3 protein. While it is well established that the ataxin-3 protein functions as a deubiquitinating (DUB) enzyme and is therefore critically involved in proteostasis, several unanswered questions remain regarding the impact of polyQ expansion in ataxin-3 on its DUB function. Here we review the current literature surrounding ataxin-3's DUB function, its DUB targets, and what is known regarding the impact of polyQ expansion on ataxin-3's DUB function. We also consider the potential neuroprotective effects of ataxin-3's DUB function, and the intersection of ataxin-3's role as a DUB enzyme and regulator of gene transcription. Ataxin-3 is the principal pathogenic protein in MJD and also appears to be involved in cancer. As aberrant deubiquitination has been linked to both neurodegeneration and cancer, a comprehensive understanding of ataxin-3's DUB function is important for elucidating potential therapeutic targets in these complex conditions. In this review, we aim to consolidate knowledge of ataxin-3 as a DUB and unveil areas for future research to aid therapeutic targeting of ataxin-3's DUB function for the treatment of MJD and other diseases.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 6","pages":"461-480"},"PeriodicalIF":4.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks. PARP 抑制剂 veliparib 的新型修饰可增加 PARP1 与 DNA 断裂的结合。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-20 DOI: 10.1042/BCJ20230406

Uday Kiran Velagapudi, Élise Rouleau-Turcotte, Ramya Billur, Xuwei Shao, Manisha Patil, Ben E Black, John M Pascal, Tanaji T Talele

{"title":"Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks.","authors":"Uday Kiran Velagapudi, Élise Rouleau-Turcotte, Ramya Billur, Xuwei Shao, Manisha Patil, Ben E Black, John M Pascal, Tanaji T Talele","doi":"10.1042/BCJ20230406","DOIUrl":"10.1042/BCJ20230406","url":null,"abstract":"Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"437-460"},"PeriodicalIF":4.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11070930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reporter cell lines to screen for inhibitors or regulators of the KRAS-RAF-MEK1/2-ERK1/2 pathway. 报告细胞系，以筛选 KRAS-RAF-MEK1/2-ERK1/2 通路的抑制剂或调节剂。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-20 DOI: 10.1042/BCJ20240015

Laura Weatherdon, Kate Stuart, Megan Cassidy, Alberto Moreno de la Gándara, Hanneke Okkenhaug, Markus Muellener, Grahame Mckenzie, Simon J Cook, Rebecca Gilley

{"title":"Reporter cell lines to screen for inhibitors or regulators of the KRAS-RAF-MEK1/2-ERK1/2 pathway.","authors":"Laura Weatherdon, Kate Stuart, Megan Cassidy, Alberto Moreno de la Gándara, Hanneke Okkenhaug, Markus Muellener, Grahame Mckenzie, Simon J Cook, Rebecca Gilley","doi":"10.1042/BCJ20240015","DOIUrl":"10.1042/BCJ20240015","url":null,"abstract":"The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is activated in cancer due to mutations in RAS proteins (especially KRAS), BRAF, CRAF, MEK1 and MEK2. Whilst inhibitors of KRASG12C (lung adenocarcinoma) and BRAF and MEK1/2 (melanoma and colorectal cancer) are clinically approved, acquired resistance remains a problem. Consequently, the search for new inhibitors (especially of RAS proteins), new inhibitor modalities and regulators of this pathway, which may be new drug targets, continues and increasingly involves cell-based screens with small molecules or genetic screens such as RNAi, CRISPR or protein interference. Here we describe cell lines that exhibit doxycycline-dependent expression KRASG12V or BRAFV600E and harbour a stably integrated EGR1:EmGFP reporter gene that can be detected by flow cytometry, high-content microscopy or immunoblotting. KRASG12V or BRAFV600E-driven EmGFP expression is inhibited by MEK1/2 or ERK1/2 inhibitors (MEKi and ERKi). BRAFi inhibit BRAFV600E-driven EmGFP expression but enhance the response to KRASG12V, recapitulating paradoxical activation of wild type RAF proteins. In addition to small molecules, expression of iDab6, encoding a RAS-specific antibody fragment inhibited KRASG12V- but not BRAFV600E-driven EmGFP expression. Finally, substitution of EmGFP for a bacterial nitroreductase gene allowed KRASG12V or BRAFV600E to drive cell death in the presence of a pro-drug, which may allow selection of pathway inhibitors that promote survival. These cell lines should prove useful for cell-based screens to identify new regulators of KRAS- or BRAF-dependent ERK1/2 signalling (drug target discovery) as well as screening or triaging 'hits' from drug discovery screens.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"405-422"},"PeriodicalIF":4.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139911924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes. AMPK 激活可抑制原代小鼠脂肪细胞中瘦素的表达，而与脂肪生成无关。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-03-06 DOI: 10.1042/BCJ20240003

Sophia Bustraan, Jane Bennett, Chad Whilding, Betheney R Pennycook, David Smith, Alexis R Barr, Jon Read, David Carling, Alice Pollard

{"title":"AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes.","authors":"Sophia Bustraan, Jane Bennett, Chad Whilding, Betheney R Pennycook, David Smith, Alexis R Barr, Jon Read, David Carling, Alice Pollard","doi":"10.1042/BCJ20240003","DOIUrl":"10.1042/BCJ20240003","url":null,"abstract":"Adipogenesis, defined as the development of mature adipocytes from stem cell precursors, is vital for the expansion, turnover and health of adipose tissue. Loss of adipogenic potential in adipose stem cells, or impairment of adipogenesis is now recognised as an underlying cause of adipose tissue dysfunction and is associated with metabolic disease. In this study, we sought to determine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved master regulator of energy homeostasis, in adipogenesis. Primary murine adipose-derived stem cells were treated with a small molecule AMPK activator (BI-9774) during key phases of adipogenesis, to determine the effect of AMPK activation on adipocyte commitment, maturation and function. To determine the contribution of the repression of lipogenesis by AMPK in these processes, we compared the effect of pharmacological inhibition of acetyl-CoA carboxylase (ACC). We show that AMPK activation inhibits adipogenesis in a time- and concentration-dependent manner. Transient AMPK activation during adipogenic commitment leads to a significant, ACC-independent, repression of adipogenic transcription factor expression. Furthermore, we identify a striking, previously unexplored inhibition of leptin gene expression in response to both short-term and chronic AMPK activation irrespective of adipogenesis. These findings reveal that in addition to its effect on adipogenesis, AMPK activation switches off leptin gene expression in primary mouse adipocytes independently of adipogenesis. Our results identify leptin expression as a novel target of AMPK through mechanisms yet to be identified.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"345-362"},"PeriodicalIF":4.1,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk. LRRK2 C 端尾部在结构域串扰中的作用

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230477

Pallavi Kaila Sharma, Jui-Hung Weng, Jascha T Manschwetus, Jian Wu, Wen Ma, Friedrich W Herberg, Susan S Taylor

{"title":"Role of the leucine-rich repeat protein kinase 2 C-terminal tail in domain cross-talk.","authors":"Pallavi Kaila Sharma, Jui-Hung Weng, Jascha T Manschwetus, Jian Wu, Wen Ma, Friedrich W Herberg, Susan S Taylor","doi":"10.1042/BCJ20230477","DOIUrl":"10.1042/BCJ20230477","url":null,"abstract":"Leucine-rich repeat protein kinase 2 (LRRK2) is a multi-domain protein encompassing two of biology's most critical molecular switches, a kinase and a GTPase, and mutations in LRRK2 are key players in the pathogenesis of Parkinson's disease (PD). The availability of multiple structures (full-length and truncated) has opened doors to explore intra-domain cross-talk in LRRK2. A helix extending from the WD40 domain and stably docking onto the kinase domain is common in all available structures. This C-terminal (Ct) helix is a hub of phosphorylation and organelle-localization motifs and thus serves as a multi-functional protein : protein interaction module. To examine its intra-domain interactions, we have recombinantly expressed a stable Ct motif (residues 2480-2527) and used peptide arrays to identify specific binding sites. We have identified a potential interaction site between the Ct helix and a loop in the CORB domain (CORB loop) using a combination of Gaussian accelerated molecular dynamics simulations and peptide arrays. This Ct-Motif contains two auto-phosphorylation sites (T2483 and T2524), and T2524 is a 14-3-3 binding site. The Ct helix, CORB loop, and the CORB-kinase linker together form a part of a dynamic 'CAP' that regulates the N-lobe of the kinase domain. We hypothesize that in inactive, full-length LRRK2, the Ct-helix will also mediate interactions with the N-terminal armadillo, ankyrin, and LRR domains (NTDs) and that binding of Rab substrates, PD mutations, or kinase inhibitors will unleash the NTDs.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"313-327"},"PeriodicalIF":4.4,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139671223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IL-4 activates the futile triacylglyceride cycle for glucose utilization in white adipocytes. IL-4 激活白色脂肪细胞中葡萄糖利用的三酰甘油循环。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230486

Svetlana Michurina, Margarita Agareva, Ekaterina Zubkova, Mikhail Menshikov, Iurii Stafeev, Yelena Parfyonova

{"title":"IL-4 activates the futile triacylglyceride cycle for glucose utilization in white adipocytes.","authors":"Svetlana Michurina, Margarita Agareva, Ekaterina Zubkova, Mikhail Menshikov, Iurii Stafeev, Yelena Parfyonova","doi":"10.1042/BCJ20230486","DOIUrl":"10.1042/BCJ20230486","url":null,"abstract":"The development of cardiometabolic complications during obesity is strongly associated with chronic latent inflammation in hypertrophied adipose tissue (AT). IL-4 is an anti-inflammatory cytokine, playing a protective role against insulin resistance, glucose intolerance and weight gain. The positive effects of IL-4 are associated not only with the activation of anti-inflammatory immune cells in AT, but also with the modulation of adipocyte metabolism. IL-4 is known to activate lipolysis and glucose uptake in adipocytes, but the precise regulatory mechanisms and physiological significance of these processes remain unclear. In this study, we detail IL-4 effects on glucose and triacylglycerides (TAGs) metabolism and propose mechanisms of IL-4 metabolic action in adipocytes. We have shown that IL-4 activates glucose oxidation, lipid droplet (LD) fragmentation, lipolysis and thermogenesis in mature 3T3-L1 adipocytes. We found that lipolysis was not accompanied by fatty acids (FAs) release from adipocytes, suggesting FA re-esterification. Moreover, glucose oxidation and thermogenesis stimulation depended on adipocyte triglyceride lipase (ATGL) activity, but not the uncoupling protein (UCP1) expression. Based on these data, IL-4 may activate the futile TAG-FA cycle in adipocytes, which enhances the oxidative activity of cells and heat production. Thus, the positive effect of IL-4 on systemic metabolism can be the result of the activation of non-canonical thermogenic mechanism in AT, increasing TAG turnover and utilization of excessive glucose.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"329-344"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139696873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism. 从 MyD88 的死亡域中鉴定出一种 10-mer 肽，它能减轻炎症和胰岛素抵抗，改善葡萄糖代谢。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230369

Mehmood Ali, Tripti Kumari, Arvind Gupta, Sariyah Akhtar, Rahul Dev Verma, Jimut Kanti Ghosh

{"title":"Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism.","authors":"Mehmood Ali, Tripti Kumari, Arvind Gupta, Sariyah Akhtar, Rahul Dev Verma, Jimut Kanti Ghosh","doi":"10.1042/BCJ20230369","DOIUrl":"10.1042/BCJ20230369","url":null,"abstract":"Insulin resistance (IR) is the key pathophysiological cause of type 2 diabetes, and inflammation has been implicated in it. The death domain (DD) of the adaptor protein, MyD88 plays a crucial role in the transduction of TLR4-associated inflammatory signal. Herein, we have identified a 10-residue peptide (M10), from the DD of MyD88 which seems to be involved in Myddosome formation. We hypothesized that M10 could inhibit MyD88-dependent TLR4-signaling and might have effects on inflammation-associated IR. Intriguingly, 10-mer M10 showed oligomeric nature and reversible self-assembly property indicating the peptide's ability to recognize its own amino acid sequence. M10 inhibited LPS-induced nuclear translocation of NF-κB in L6 myotubes and also reduced LPS-induced IL-6 and TNF-α production in peritoneal macrophages of BALB/c mice. Remarkably, M10 inhibited IL-6 and TNF-α secretion in diabetic, db/db mice. Notably, M10 abrogated IR in insulin-resistant L6 myotubes, which was associated with an increase in glucose uptake and a decrease in Ser307-phosphorylation of IRS1, TNF-α-induced JNK activation and nuclear translocation of NF-κB in these cells. Alternate day dosing with M10 (10 and 20 mg/kg) for 30 days in db/db mice significantly lowered blood glucose and improved glucose intolerance after loading, 3.0 g/kg glucose orally. Furthermore, M10 increased insulin and adiponectin secretion in db/db mice. M10-induced glucose uptake in L6 myotubes involved the activation of PI3K/AKT/GLUT4 pathways. A scrambled M10-analog was mostly inactive. Overall, the results show the identification of a 10-mer peptide from the DD of MyD88 with anti-inflammatory and anti-diabetic properties, suggesting that targeting of TLR4-inflammatory pathway, could lead to the discovery of molecules against IR and diabetes.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"191-218"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139471830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 role of filamentous matrix molecules in shaping the architecture and emergent properties of bacterial biofilms. 丝状基质分子在塑造细菌生物膜的结构和新兴特性中的作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20210301

Jan Böhning, Abul K Tarafder, Tanmay A M Bharat

引用次数: 0