FEBS LettersPub Date : 2024-09-08DOI: 10.1002/1873-3468.15012
Gerd Van der Hoeven, Sarah Lemaire, Xinyu Cao, Zander Claes, Spyridoula Karamanou, Mathieu Bollen
{"title":"Spontaneous and chaperone-assisted metal loading in the active site of protein phosphatase-1.","authors":"Gerd Van der Hoeven, Sarah Lemaire, Xinyu Cao, Zander Claes, Spyridoula Karamanou, Mathieu Bollen","doi":"10.1002/1873-3468.15012","DOIUrl":"https://doi.org/10.1002/1873-3468.15012","url":null,"abstract":"<p><p>Protein phosphatase PP1 has two active-site metals (Zn<sup>2+</sup>/Fe<sup>2+</sup>) that are essential for catalysis. However, when expressed in bacteria, PP1 has two Mn<sup>2+</sup>-ions in its active site, indicating that the incorporation of Zn<sup>2+</sup>/Fe<sup>2+</sup> depends on additional eukaryotic component(s). Here, we used purified, metal-deficient PP1 to study metal incorporation. Fe<sup>2+</sup> was incorporated spontaneously, but Zn<sup>2+</sup> was not. Mn<sup>2+</sup>-incorporation at physiological pH depended on the co-expression of PP1 with PPP1R2 (Inhibitor-2) or PPP1R11 (Inhibitor-3), or a pre-incubation of PP1 at pH 4. We also demonstrate that PPP1R2 and PPP1R11 are Zn<sup>2+</sup>-binding proteins but are, by themselves, not able to load PP1 with Zn<sup>2+</sup>. Our data suggest that PPP1R2 and PPP1R11 function as metal chaperones for PP1 but depend on co-chaperone(s) and/or specific modification(s) for the transfer of associated Zn<sup>2+</sup> to PP1.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-09-03DOI: 10.1002/1873-3468.15008
Lishu Guo
{"title":"Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.","authors":"Lishu Guo","doi":"10.1002/1873-3468.15008","DOIUrl":"https://doi.org/10.1002/1873-3468.15008","url":null,"abstract":"<p><p>The opening of the mitochondrial permeability transition pore (PTP), a Ca<sup>2+</sup>-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-09-01DOI: 10.1002/1873-3468.15006
Carlos Camilleri-Robles, Paula Climent-Cantó, Palmira Llorens-Giralt, Cecilia C Klein, Florenci Serras, Montserrat Corominas
{"title":"A shift in chromatin binding of phosphorylated p38 precedes transcriptional changes upon oxidative stress.","authors":"Carlos Camilleri-Robles, Paula Climent-Cantó, Palmira Llorens-Giralt, Cecilia C Klein, Florenci Serras, Montserrat Corominas","doi":"10.1002/1873-3468.15006","DOIUrl":"https://doi.org/10.1002/1873-3468.15006","url":null,"abstract":"<p><p>P38 mitogen-activated protein kinases are key in the regulation of the cellular response to stressors. P38 is known to regulate transcription, mRNA processing, stability, and translation. The transcriptional changes mediated by phosphorylated p38 (P-p38) in response to extracellular stimuli have been thoroughly analyzed in many tissues and organisms. However, the genomic localization of chromatin-associated P-p38 remains poorly understood. Here, we analyze the chromatin binding of activated P-p38 and its role in the response to reactive oxygen species (ROS) in Drosophila S2 cells. We found that P-p38 is already bound to chromatin in basal conditions. After ROS exposure, chromatin-associated P-p38 relocates towards genes involved in the recovery process. Our findings highlight the role of P-p38 dynamic chromatin binding in orchestrating gene expression responses to oxidative stress.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-08-28DOI: 10.1002/1873-3468.15007
Naomi Berkowitz, Allison MacMillan, Marit B Simmons, Ujwal Shinde, Georgiana E Purdy
{"title":"Structural modeling and characterization of the Mycobacterium tuberculosis MmpL3 C-terminal domain.","authors":"Naomi Berkowitz, Allison MacMillan, Marit B Simmons, Ujwal Shinde, Georgiana E Purdy","doi":"10.1002/1873-3468.15007","DOIUrl":"https://doi.org/10.1002/1873-3468.15007","url":null,"abstract":"<p><p>The Mycobacterium tuberculosis (Mtb) cell envelope provides a protective barrier against the immune response and antibiotics. The mycobacterial membrane protein large (MmpL) family of proteins export cell envelope lipids and siderophores; therefore, these proteins are important for the basic biology and pathogenicity of Mtb. In particular, MmpL3 is essential and a known drug target. Despite interest in MmpL3, the structural data in the field are incomplete. Utilizing homology modeling, AlphaFold, and biophysical techniques, we characterized the cytoplasmic C-terminal domain (CTD) of MmpL3 to better understand its structure and function. Our in silico models of the MmpL11<sub>TB</sub> and MmpL3<sub>TB</sub> CTD reveal notable features including a long unstructured linker that connects the globular domain to the last transmembrane (TM) in each transporter, charged lysine and arginine residues facing the membrane, and a C-terminal alpha helix. Our predicted overall structure enables a better understanding of these transporters.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural basis of sugar recognition by SCF<sup>FBS2</sup> ubiquitin ligase involved in NGLY1 deficiency.","authors":"Tadashi Satoh, Maho Yagi-Utsumi, Nozomi Ishii, Tsunehiro Mizushima, Hirokazu Yagi, Ryuichi Kato, Yuriko Tachida, Hiroaki Tateno, Ichiro Matsuo, Koichi Kato, Tadashi Suzuki, Yukiko Yoshida","doi":"10.1002/1873-3468.15003","DOIUrl":"https://doi.org/10.1002/1873-3468.15003","url":null,"abstract":"<p><p>The cytosolic peptide:N-glycanase (PNGase) is involved in the quality control of N-glycoproteins via the endoplasmic reticulum-associated degradation (ERAD) pathway. Mutations in the gene encoding cytosolic PNGase (NGLY1 in humans) cause NGLY1 deficiency. Recent findings indicate that the F-box protein FBS2 of the SCF<sup>FBS2</sup> ubiquitin ligase complex can be a promising drug target for NGLY1 deficiency. Here, we determined the crystal structure of bovine FBS2 complexed with the adaptor protein SKP1 and a sugar ligand, Man<sub>3</sub>GlcNAc<sub>2</sub>, which corresponds to the core pentasaccharide of N-glycan. Our crystallographic data together with NMR data revealed the structural basis of disparate sugar-binding specificities in homologous FBS proteins and identified a potential druggable pocket for in silico docking studies. Our results provide a potential basis for the development of selective inhibitors against FBS2 in NGLY1 deficiency.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Metabolic dysregulation-triggered neutrophil extracellular traps exacerbate acute liver failure.","authors":"Kangnan Zhang, Rongrong Jia, Qinghui Zhang, Shihao Xiang, Na Wang, Ling Xu","doi":"10.1002/1873-3468.14971","DOIUrl":"https://doi.org/10.1002/1873-3468.14971","url":null,"abstract":"<p><p>Acute liver failure (ALF) is an acute liver disease with a high mortality rate in clinical practice, characterized histologically by extensive hepatocellular necrosis and massive neutrophil infiltration. However, the role of these abnormally infiltrating neutrophils during ALF development is unclear. Here, in an ALF mouse model, metabolites were identified that promote the formation of neutrophil extracellular traps (NETs) in the liver, subsequently influencing macrophage differentiation and disease progression. ALF occurs with abnormalities in hepatic and intestinal metabolites. Abnormal metabolites (LTD4 and glutathione) can directly, or indirectly via reactive oxygen species, promote NET formation of infiltrating neutrophils, which subsequently regulate macrophages in a pro-inflammatory M1-like state, inducing an amplification of the destructive effects of inflammation. Together, this study provides new insights into the role of NETs in the pathogenesis of ALF.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The miR-26a/SIRT6/HIF-1α axis regulates glycolysis and inflammatory responses in host macrophages during Mycobacterium tuberculosis infection.","authors":"Soumya Mal, Debayan Majumder, Pankaj Birari, Arun Kumar Sharma, Umesh Gupta, Kuladip Jana, Manikuntala Kundu, Joyoti Basu","doi":"10.1002/1873-3468.15001","DOIUrl":"https://doi.org/10.1002/1873-3468.15001","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb-triggered regulation of the innate immune response. Mtb infection downregulated microRNA-26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF-1α-dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF-1α, as well as the release of interleukin (IL)-1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL-6 but augmented anti-inflammatory arginase expression. The miR-26a/SIRT6/HIF-1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-08-16DOI: 10.1002/1873-3468.15004
Sandra Cotino-Nájera, Enrique García-Villa, Samantha Cruz-Rosales, Patricio Gariglio, José Díaz-Chávez
{"title":"The role of Lin28A and Lin28B in cancer beyond Let-7.","authors":"Sandra Cotino-Nájera, Enrique García-Villa, Samantha Cruz-Rosales, Patricio Gariglio, José Díaz-Chávez","doi":"10.1002/1873-3468.15004","DOIUrl":"https://doi.org/10.1002/1873-3468.15004","url":null,"abstract":"<p><p>Lin28A and Lin28B are paralogous RNA-binding proteins that play fundamental roles in development and cancer by regulating the microRNA family of tumor suppressor Let-7. Although Lin28A and Lin28B share some functional similarities with Let-7 inhibitors, they also have distinct expression patterns and biological functions. Increasing evidence indicates that Lin28A and Lin28B differentially impact cancer stem cell properties, epithelial-mesenchymal transition, metabolic reprogramming, and other hallmarks of cancer. Therefore, it is important to understand the overexpression of Lin28A and Lin28B paralogs in specific cancer contexts. In this review, we summarize the main similarities and differences between Lin28A and Lin28B, their implications in different cellular processes, and their role in different types of cancer. In addition, we provide evidence of other specific targets of each lin28 paralog, as well as the lncRNAs and miRNAs that promote or inhibit its expression, and how this impacts cancer development and progression.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-08-16DOI: 10.1002/1873-3468.15000
Mateo N Diaz Appella, Adriana Kolender, Oscar J Oppezzo, Nancy I López, Paula M Tribelli
{"title":"The structural complexity of pyomelanin impacts UV shielding in Pseudomonas species with different lifestyles.","authors":"Mateo N Diaz Appella, Adriana Kolender, Oscar J Oppezzo, Nancy I López, Paula M Tribelli","doi":"10.1002/1873-3468.15000","DOIUrl":"https://doi.org/10.1002/1873-3468.15000","url":null,"abstract":"<p><p>Pyomelanin, a polymeric pigment in Pseudomonas, arises mainly from alterations in tyrosine degradation. The chemical structure of pyomelanin remains elusive due to its heterogeneous nature. Here, we report strain-specific differences in pyomelanin structural features across Pseudomonas using PAO1 and PA14 reference strains carrying mutations in hmgA (a gene involved in pyomelanin synthesis), a melanogenic P. aeruginosa clinical isolate (PAM), and a melanogenic P. extremaustralis (PexM). UV spectra showed dual peaks for PAO1 and PA14 mutants and single peaks for PAM and PexM. FTIR phenol : alcohol ratio changes and complex NMR spectra indicated non-linear polymers. UVC radiation survival increased with pyomelanin addition, correlating with pigment absorption attenuation. P. extremaustralis UVC survival varied with melanin source, with PAO1 pyomelanin being the most protective. These findings delineate structure-based pyomelanin subgroups, having distinct physiological effects.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS LettersPub Date : 2024-08-16DOI: 10.1002/1873-3468.14996
Mohammad Khoonkari, Dong Liang, Marleen Kamperman, Patrick van Rijn, Frank A E Kruyt
{"title":"The unfolded protein response sensor PERK mediates mechanical stress-induced maturation of focal adhesion complexes in glioblastoma cells.","authors":"Mohammad Khoonkari, Dong Liang, Marleen Kamperman, Patrick van Rijn, Frank A E Kruyt","doi":"10.1002/1873-3468.14996","DOIUrl":"https://doi.org/10.1002/1873-3468.14996","url":null,"abstract":"<p><p>Stiffening of the brain extracellular matrix (ECM) in glioblastoma promotes tumor progression. Previously, we discovered that protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) plays a role in glioblastoma stem cell (GSC) adaptation to matrix stiffness through PERK/FLNA-dependent F-actin remodeling. Here, we examined the involvement of PERK in detecting stiffness changes via focal adhesion complex (FAC) formation. Compared to control GSCs, PERK-deficient GSCs show decreased vinculin and tensin expression, while talin and integrin-β1 remain constant. Furthermore, vimentin was also reduced while tubulin increased, and a stiffness-dependent increase of the differentiation marker GFAP expression was absent in PERK-deficient GSCs. In conclusion, our study reveals a novel role for PERK in FAC formation during matrix stiffening, which is likely linked to its regulation of F-actin remodeling.</p>","PeriodicalId":12142,"journal":{"name":"FEBS Letters","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}