@article{MTMT:33604376, title = {Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging}, url = {https://m2.mtmt.hu/api/publication/33604376}, author = {Jiao, J. and Curley, M. and Graca, F.A. and Robles-Murguia, M. and Shirinifard, A. and Finkelstein, D. and Xu, B. and Fan, Y. and Demontis, F.}, doi = {10.1016/j.celrep.2022.111970}, journal-iso = {CELL REP}, journal = {CELL REPORTS}, volume = {42}, unique-id = {33604376}, issn = {2211-1247}, abstract = {Protein quality control is important for healthy aging and is dysregulated in age-related diseases. The autophagy-lysosome and ubiquitin-proteasome are key for proteostasis, but it remains largely unknown whether other proteolytic systems also contribute to maintain proteostasis during aging. Here, we find that expression of proteolytic enzymes (proteases/peptidases) distinct from the autophagy-lysosome and ubiquitin-proteasome systems declines during skeletal muscle aging in Drosophila. Age-dependent protease downregulation undermines proteostasis, as demonstrated by the increase in detergent-insoluble poly-ubiquitinated proteins and pathogenic huntingtin-polyQ levels in response to protease knockdown. Computational analyses identify the transcription factor Ptx1 (homologous to human PITX1/2/3) as a regulator of protease expression. Consistent with this model, Ptx1 protein levels increase with aging, and Ptx1 RNAi counteracts the age-associated downregulation of protease expression. Moreover, Ptx1 RNAi improves muscle protein quality control in a protease-dependent manner and extends lifespan. These findings indicate that proteases and their transcriptional modulator Ptx1 ensure proteostasis during aging. © 2022 The Author(s)}, keywords = {Male; PROTEASE; TRANSCRIPTION FACTOR; ARTICLE; DROSOPHILA; TRYPSIN; protein analysis; controlled study; nonhuman; animal tissue; animal experiment; skeletal muscle; skeletal muscle; Aging; Aging; RNA Interference; quality control; PROTEIN FUNCTION; unclassified drug; protein expression; proteinase; lysosome; UBIQUITIN; polyglutamine; upregulation; lifespan; proteasome; down regulation; Retina; peptidase; peptidase; protein degradation; protein aggregation; Huntingtin; Huntingtin; Ubiquitination; protein homeostasis; Protein quality control; protein quality; polyubiquitination; gene knockdown; Proteostasis; autophagy (cellular); pitx; CP: Cell Biology; CP: Molecular biology; betaTry; Ptx1; beta trypsin; transcription factor Ptx1}, year = {2023}, eissn = {2211-1247} } @article{MTMT:32620017, title = {The Downregulation of Both Giant HERCs, HERC1 and HERC2, Is an Unambiguous Feature of Chronic Myeloid Leukemia, and HERC1 Levels Are Associated with Leukemic Cell Differentiation}, url = {https://m2.mtmt.hu/api/publication/32620017}, author = {Ali, M.S. and Magnati, S. and Panuzzo, C. and Cilloni, D. and Saglio, G. and Pergolizzi, B. and Bracco, E.}, doi = {10.3390/jcm11020324}, journal-iso = {J CLIN MED}, journal = {JOURNAL OF CLINICAL MEDICINE}, volume = {11}, unique-id = {32620017}, abstract = {Large HERC E3 ubiquitin ligase family members, HERC1 and HERC2, are staggeringly complex proteins that can intervene in a wide range of biological processes, such as cell proliferation, DNA repair, neurodevelopment, and inflammation. Therefore, mutations or dysregulation of large HERCs is associated with neurological disorders, DNA repair defects, and cancer. Though their role in solid tumors started to be investigated some years ago, our knowledge about HERCs in non-solid neoplasm is greatly lagging behind. Chronic Myeloid Leukemia (CML) is a model onco-hematological disorder because of its unique and unambiguous relation between genotype and phenotype due to a single genetic alteration. In the present study, we ascertained that the presence of the BCR-ABL fusion gene was inversely associated with the expression of the HERC1 and HERC2 genes. Upon the achievement of remission, both HERC1 and HERC2 mRNAs raised again to levels comparable to those of the healthy donors. Additionally, our survey unveiled that their gene expression is sensitive to different Tyrosine Kinases Inhibitors (TKIs) in a time-dependent fashion. Interestingly, for the first time, we also observed a differential HERC1 expression when the leukemic cell lines were induced to differentiate towards different lineages revealing that HERC1 protein expression is associated with the differentiation process in a lineage-specific manner. Taken together, our findings suggest that HERC1 might act as a novel potential player in blood cell differentiation. Overall, we believe that our results are beneficial to initiate exploring the role/s of large HERCs in non-solid neoplasms. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.}, keywords = {DIFFERENTIATION; CML; UBIQUITIN SYSTEM; TKIs; Large HERCs}, year = {2022}, eissn = {2077-0383} } @article{MTMT:32853674, title = {Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration}, url = {https://m2.mtmt.hu/api/publication/32853674}, author = {Rai, M. and Curley, M. and Coleman, Z. and Demontis, F.}, doi = {10.1111/acel.13603}, journal-iso = {AGING CELL}, journal = {AGING CELL}, volume = {21}, unique-id = {32853674}, issn = {1474-9718}, abstract = {Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age-associated diseases. The ubiquitin–proteasome and autophagy-lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age-related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy-lysosome and ubiquitin–proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age-related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age-related neurodegeneration. © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.}, keywords = {PROTEASE; PROTEOLYSIS; Aging; neurodegeneration; peptidase; extracellular proteostasis}, year = {2022}, eissn = {1474-9726} } @article{MTMT:33063331, title = {STABILON, a Novel Sequence Motif That Enhances the Expression and Accumulation of Intracellular and Secreted Proteins}, url = {https://m2.mtmt.hu/api/publication/33063331}, author = {Réthi-Nagy, Zsuzsánna and Ábrahám, Edit and Udvardy, Katalin and Klement, Éva and Darula, Zsuzsanna and Pál, Margit and Katona, Robert L. and Tubak, Vilmos and Páli, Tibor and Kóta, Zoltán and Sinka, Rita and Udvardy, Andor and Lipinszki, Zoltán}, doi = {10.3390/ijms23158168}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {33063331}, issn = {1661-6596}, abstract = {The dynamic balance of transcriptional and translational regulation together with degron-controlled proteolysis shapes the ever-changing cellular proteome. While a large variety of degradation signals has been characterized, our knowledge of cis-acting protein motifs that can in vivo stabilize otherwise short-lived proteins is very limited. We have identified and characterized a conserved 13-mer protein segment derived from the p54/Rpn10 ubiquitin receptor subunit of the Drosophila 26S proteasome, which fulfills all the characteristics of a protein stabilization motif (STABILON). Attachment of STABILON to various intracellular as well as medically relevant secreted model proteins resulted in a significant increase in their cellular or extracellular concentration in mammalian cells. We demonstrate that STABILON acts as a universal and dual function motif that, on the one hand, increases the concentration of the corresponding mRNAs and, on the other hand, prevents the degradation of short-lived fusion proteins. Therefore, STABILON may lead to a breakthrough in biomedical recombinant protein production.}, keywords = {SYSTEM; SUBUNIT; DROSOPHILA; Protein Stability; ENHANCER; proteasome; protein degradation; SECRETED PROTEINS; Biochemistry & Molecular Biology; Protein production; mRNA stability; stabilization motif}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {Páli, Tibor/0000-0003-1649-1097; Kóta, Zoltán/0000-0003-2420-8773; Sinka, Rita/0000-0003-4040-4184; Lipinszki, Zoltán/0000-0002-2067-0832} } @article{MTMT:32008450, title = {Proteasome stress in skeletal muscle mounts a long-range protective response that delays retinal and brain aging}, url = {https://m2.mtmt.hu/api/publication/32008450}, author = {Rai, M. and Coleman, Z. and Curley, M. and Nityanandam, A. and Platt, A. and Robles-Murguia, M. and Jiao, J. and Finkelstein, D. and Wang, Y.-D. and Xu, B. and Fan, Y. and Demontis, F.}, doi = {10.1016/j.cmet.2021.03.005}, journal-iso = {CELL METAB}, journal = {CELL METABOLISM}, volume = {33}, unique-id = {32008450}, issn = {1550-4131}, abstract = {Neurodegeneration in the central nervous system (CNS) is a defining feature of organismal aging that is influenced by peripheral tissues. Clinical observations indicate that skeletal muscle influences CNS aging, but the underlying muscle-to-brain signaling remains unexplored. In Drosophila, we find that moderate perturbation of the proteasome in skeletal muscle induces compensatory preservation of CNS proteostasis during aging. Such long-range stress signaling depends on muscle-secreted Amyrel amylase. Mimicking stress-induced Amyrel upregulation in muscle reduces age-related accumulation of poly-ubiquitinated proteins in the brain and retina via chaperones. Preservation of proteostasis stems from the disaccharide maltose, which is produced via Amyrel amylase activity. Correspondingly, RNAi for SLC45 maltose transporters reduces expression of Amyrel-induced chaperones and worsens brain proteostasis during aging. Moreover, maltose preserves proteostasis and neuronal activity in human brain organoids challenged by thermal stress. Thus, proteasome stress in skeletal muscle hinders retinal and brain aging by mounting an adaptive response via amylase/maltose. © 2021 Elsevier Inc.}, keywords = {MALTOSE; Aging; proteasome; amylase; stress response; Proteostasis; Myokine; brain organoids; muscle-to-brain signaling; muscle-to-retina signaling}, year = {2021}, eissn = {1932-7420}, pages = {1137-+} } @article{MTMT:30514897, title = {The proteome map of the escamolera ant (Liometopum apiculatum Mayr) larvae reveals immunogenic proteins and several hexamerin proteoforms}, url = {https://m2.mtmt.hu/api/publication/30514897}, author = {Huerta-Ocampo, Jose A. and Garcia-Munoz, Maria S. and Velarde-Salcedo, Aida J. and Hernandez-Dominguez, Eric E. and Gonzalez-Escobar, Jorge L. and Barrera-Pacheco, Alberto and Grajales-Lagunes, Alicia and Barba de la Rosa, Ana P.}, doi = {10.1016/j.cbd.2018.07.004}, journal-iso = {COMP BIOCHEM PHYS D}, journal = {COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS}, volume = {28}, unique-id = {30514897}, issn = {1744-117X}, abstract = {The larvae of escamolera ant (Liometopum apiculatum Mayr) have been considered a delicacy since Pre-Hispanic times. The increased demand for this stew has led to massive collection of ant nests. Yet biological aspects of L. apiculatum larvae remain unknown, and mapping the proteome of this species is important for understanding its biological characteristics. Two-dimensional gel electrophoresis (2-DE) followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was used to characterize the larvae proteome profile. From 380 protein spots analyzed, 174 were identified by LC-MS/MS and homology search against the Hymenoptera subset of the NCBInr protein database using the Mascot search engine. Peptide de novo sequencing and homology-based alignment allowed the identification of 36 additional protein spots. Identified proteins were classified by cellular location, molecular function, and biological process according to the Gene Ontology annotation. Immunity- and defense-related proteins were identified including PPlases, FK506, PEBP, and chitinases. Several hexamerin proteoforms were identified and the cDNA of the most abundant protein detected in the 2-DE map was isolated and characterized. L. apiculatum hexamerin (LaHEX, GeneBank accession no. MH256667) contains an open reading frame of 2199 bp encoding a polypeptide of 733 amino acid residues with a calculated molecular mass of 82.41 kDa. LaHEX protein is more similar to HEX110 than HEX70 from Apis mellifera. Down-regulation of LaHEX was observed throughout ant development. This work represents the first proteome map as well as the first hexamerin characterized from L. apiculatum larvae.}, keywords = {GENE ONTOLOGY; LC-MS/MS; Two-dimensional gel electrophoresis; qRT-PCR; Escamoles; Peptide de novo sequencing}, year = {2018}, eissn = {1878-0407}, pages = {107-121} } @article{MTMT:24984082, title = {An intrinsically disordered region of RPN10 plays a key role in restricting ubiquitin chain elongation in RPN10 monoubiquitination}, url = {https://m2.mtmt.hu/api/publication/24984082}, author = {Puig-Sàrries, P and Bijlmakers, M-J and Zuin, A and Bichmann, A and Pons, M and Crosas, B}, doi = {10.1042/BJ20141571}, journal-iso = {BIOCHEM J}, journal = {BIOCHEMICAL JOURNAL}, volume = {469}, unique-id = {24984082}, issn = {0264-6021}, year = {2015}, eissn = {1470-8728}, pages = {455-467} } @article{MTMT:2723940, title = {Affinity purification of protein complexes from Drosophila embryos in cell cycle studies.}, url = {https://m2.mtmt.hu/api/publication/2723940}, author = {Lipinszki, Zoltán and Wang, P and Grant, R and Lindon, C and Dzhindzhev, NS and D'Avino, PP and Przewloka, MR and Glover, DM and Archambault, V}, doi = {10.1007/978-1-4939-0888-2_33}, journal-iso = {METHODS MOL BIOL}, journal = {METHODS IN MOLECULAR BIOLOGY}, volume = {1170}, unique-id = {2723940}, issn = {1064-3745}, abstract = {The ability to identify protein interactions is key to elucidating the molecular mechanisms of cellular processes, including mitosis and cell cycle regulation. Drosophila melanogaster, as a model system, provides powerful tools to study cell division using genetics, microscopy, and RNAi. Drosophila early embryos are highly enriched in mitotic protein complexes as their nuclei undergo 13 rounds of rapid, synchronous mitotic nuclear divisions in a syncytium during the first 2 h of development. Here, we describe simple methods for the affinity purification of protein complexes from transgenic fly embryos via protein A- and green fluorescent protein-tags fused to bait proteins of interest. This in vivo proteomics approach has allowed the identification of several known and novel mitotic protein interactions using mass spectrometry, and it expands the use of the Drosophila model in modern molecular biology.}, keywords = {PROTEIN; GENETICS; green fluorescent protein; ARTICLE; MICROSCOPY; DROSOPHILA; Cell Division; priority journal; Cell Nucleus; nonhuman; animal experiment; Mitosis; Mass spectrometry; Cell Cycle; RNA Interference; Drosophila melanogaster; EMBRYOS; embryo; in vivo study; protein purification; Molecular Biology; proteomics; affinity purification; protein interaction; Protein A; PROTEIN COMPLEXES; Interactions; protein tag}, year = {2014}, eissn = {1940-6029}, pages = {571-588}, orcid-numbers = {Lipinszki, Zoltán/0000-0002-2067-0832} }