Ciechanover, A

Moral clarity at WHO needs to be clearer Moral clarity at WHO needs to be clearer Lancet. 2024 Feb 16:S0140-6736(24)00065-5. doi: 10.1016/S0140-6736(24)00065-5. Online ahead of print. Authors Rafael Beyar 1 , Shraga Blazer 2 , Edward Breuer 3 , Rivka Carmi 4 , Aaron Ciechanover 5 , A Mark Clarfield 6 , Shimon Glick 7 , Daniella Magen 1 , Orly Manor 8 , Ora Paltiel 8 , Karl Skorecki 9 Affiliations 1 Rambam Health Care Campus, Haifa, Israel; Technion-Israel Institute of Technology, Haifa, Israel. 2 Rambam Health Care Campus, Haifa, Israel. 3 Hebrew University of Jersualem, Jerusalem, Israel. 4 Israeli Academy for Science in Medicine, Ramat Gan, Israel. 5 Technion-Israel Institute of Technology, Haifa, Israel. 6 Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel. Electronic address: markclar@bgu.ac.il. 7 Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel. 8 Hebrew University-…

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes responsible for linking a transfer RNA (tRNA) with its cognate amino acid present in all the kingdoms of life. Besides their aminoacyl-tRNA synthetase activity, it was described that many of these enzymes can carry out non-canonical functions. They were shown to be involved in important biological processes such as metabolism, immunity, development, angiogenesis and tumorigenesis. In the present work, we provide evidence that tryptophanyl-tRNA synthetase might be involved in a negative feedback loop mitigating the expression of certain interferon-γ-induced genes. Mining the available TCGA and Gtex data, we found that WARS was highly expressed in cutaneous melanoma (SKCM) compared to other cancers and is of good prognosis for this particular cancer type. WARS expression correlates with genes involved in antigen processing and presentation but also transcription factors involved in IFN-γ signaling such as STAT1. In addition, WARS was found in complex with STAT1 in A375 cells treated with IFN-γ. Finally, we showed that knocking down WARS expression during IFN-γ stimulation further increases the expression of GBP2, APOL1, ISG15, HLA-A and IDO1.

The ubiquitin–proteasome system (UPS) is an essential mechanism responsible for the selective degradation of substrate proteins via their conjugation with ubiquitin. Since cardiomyocytes have very limited self-renewal capacity, as they are prone to protein damage due to constant mechanical and metabolic stress, the UPS has a key role in cardiac physiology and pathophysiology. While altered proteasomal activity contributes to a variety of cardiac pathologies, such as heart failure and ischemia/reperfusion injury (IRI), the environmental cues affecting its activity are still unknown, and they are the focus of this work. Following a recent study by Ciechanover’s group showing that amino acid (AA) starvation in cultured cancer cell lines modulates proteasome intracellular localization and activity, we tested two hypotheses in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs, CMs):(i) AA starvation causes proteasome translocation in CMs, similarly to the observation in cultured cancer cell lines;(ii) manipulation of subcellular proteasomal compartmentalization is associated with electrophysiological abnormalities in the form of arrhythmias, mediated via altered intracellular Ca2+ handling. The major findings are:(i) starving CMs to AAs results in proteasome translocation from the nucleus to the cytoplasm, while supplementation with the aromatic amino acids tyrosine (Y), tryptophan (W) and phenylalanine (F)(YWF) inhibits the proteasome recruitment;(ii) AA-deficient treatments cause arrhythmias;(iii) the arrhythmias observed upon nuclear proteasome sequestration (-AA+ YWF) are blocked by KB-R7943, an inhibitor of the reverse …

The invention provides a method for treating cancer comprising the step of administering a therapeutically effective amount of KPC1, a peptide which is at least about 70% homologous to the KPC1 or an agent which up-regulates KPC1. In some embodiments, there is also provided a method for treating cancer comprising the step of administering a therapeutically effective amount of p50, a peptide which is at least about 70% homologous to the p50 or an agent which up-regulates p50.

The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational modifications) have been unraveled, studying its adaptive compartmentalization in response to stress is just starting to emerge. We found that following amino acid starvation, the proteasome is translocated from its large nuclear pool to the cytoplasm—a response regulated by newly identified mTOR-agonistic amino acids—Tyr, Trp, and Phe (YWF). YWF relay their signal upstream of mTOR through Sestrin3 by disrupting its interaction with the GATOR2 complex. The triad activates mTOR toward its downstream substrates p62 and transcription factor EB (TFEB), affecting both proteasomal and autophagic activities. Proteasome translocation stimulates cytosolic proteolysis which replenishes amino acids, thus enabling cell survival. In contrast, nuclear …

The chemokine receptor CXCR4 has become an attractive therapeutic target for HIV-1 infection, hematopoietic stem cell mobilization, and cancer metastasis. A wide variety of synthetic antagonists of CXCR4 have been developed and studied for a growing list of clinical applications. To compare the biological effects of different antagonists on CXCR4 functions and their common and/or distinctive molecular interactions with the receptor, we conducted head-to-head comparative cell-based biological and mutational analyses of the interactions with CXCR4 of eleven reported antagonists, including HC4319, DV3, DV1, DV1 dimer, V1, vMIP-II, CVX15, LY2510924, IT1t, AMD3100, and AMD11070 that were representative of different structural classes of D-peptides, L-peptide, natural chemokine, cyclic peptides, and small molecules. The results were rationalized by molecular modeling of CXCR4–antagonist interactions …

Proteins are the engines of all forms of life, for humans and for all the plant and animal kingdoms. Proteins are used both to build organs (such as bones, muscles, and skin) and to perform bodily functions. These functions range from digestion (processing food and converting it into energy), to enabling movement and sensation (sight and hearing), to protecting the body from foreign invaders with our antibodies, which are also proteins. What are proteins? They can be compared to words in a language that contains letters. In the Hebrew alphabet, there are letters out of which countless words can be composed. But when we write, we use just a fraction of these infinite options, with the average number of letters in a word ranging between and. The biological “protein alphabet” is comprised of “letters” called amino acids, which are the building blocks of the proteins that make up the body. Proteins are chains of amino acid, linked together in a specific order governed by the DNA. Unlike the words of a spoken language, the average protein consists of hundreds of amino acids. The extensive length of proteins and the kids. frontiersin. org September| Volume| Article| 63

The ubiquitin-proteasome system (UPS) is responsible for up to 90% of intracellular protein degradation. Alterations in UPS are extensively involved in the development and advancement of malignant pathologies. Thus, the components of the UPS can become potential targets for cancer therapeutics. KPC1 is an E3 ubiquitin ligase component of the UPS that regulates key pathways and processes in cancer. KPC1 sustains the ubiquitination of cytoplasmic p27, determining its elimination and transition between cell-cycle phases. KPC1 also regulates NF-κB signaling by inducing ubiquitination of p105 to allow subsequent proteasomal processing to the functional form p50. It has been shown that the KPC1-p50 duo is reduced or absent in multiple malignancies and that therapeutic reinforcement of the functional axis can exhibit significant tumor suppressor activity. Here, we highlight the potential role of KPC1 as …

Huntington’s disease (HD) is caused by a glutamine repeat expansion in the protein huntingtin. The mutated protein (mHtt) forms aggregates whose impacts on neuronal survival are still debated. Using weeks-long, continual imaging of individual cortical neurons, we find that mHtt is gradually sequestrated into peripheral, mainly axonal aggregates, concomitant with dramatic reductions in cytosolic mHtt levels and enhanced neuronal survival. in-situ pulse-chase imaging reveals that aggregates continually gain and lose mHtt, in line with these acting as mHtt sinks at equilibrium with cytosolic pools. Preventing ubiquitination at two N-terminal lysines observed only in HD animal models suppresses peripheral aggregate formation and reductions in cytosolic mHtt, promotes nuclear aggregate formation, stabilizes aggregates and leads to pervasive neuronal death. These findings demonstrate the capacity of aggregates formed at peripheral locations to sequester away cytosolic, presumably toxic mHtt forms and support a crucial role for N-terminal ubiquitination in promoting these processes and delaying neuronal death.

The revolution of precision medicine, combined with artificial intelligence–based analysis of big data and exciting new technologies like CRISPR-Cas9, may change the face of clinical practice and treatment outcome of most diseases., In addition, gender- and sex-conscious medicine, which focuses on the often fundamental differences in the function of various body systems in men and in women, complements precision medicine. Now, it will be possible to diagnose diseases more precisely and to treat each patient based on his/her own “individual” disease etiology. Surprisingly, the obstacles on this path are not of a technical nature but rather related to affordability, accessibility of treatment, and most importantly, ethical issues. Thus, society will not escape the need to provide solutions to this and multiple other bioethical problems that will arise as more information, related to present or future health issues which …

Multiple myeloma (MM) is a malignant plasma cell disorder accounting for around 1.8% of all neoplastic diseases. Nowadays, clinicians have a broad arsenal of drugs at their disposal for the treatment of MM, such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, bispecific antibodies, CAR T-cell therapies and antibody-drug conjugates. In this paper we briefly highlight essential clinical elements relating to proteasome inhibitors, such as bortezomib, carfilzomib and ixazomib. Studies suggest that the early use of immunotherapy may improve outcomes significantly. Therefore, in our review we specifically focus on the combination therapy of proteasome inhibitors with novel immunotherapies and/or transplant. A high number of patients develop PI resistance. Thus, we also review new generation PIs, such as marizomib, oprozomib (ONX0912) and delanzomib (CEP-18770) and their …

The present disclosure provides mTOR agonists that selectively modulate proteasome dynamics, compositions, methods and uses thereof for modulation of stress-induced proteasome dynamics and related pathological conditions. The present disclosure specifically provides therapeutic methods for treating disorders associated with cytosolic accumulation of the proteasome. The invention further provides prognostic methods for detection and monitoring drug resistant cancers, as well as methods for screening for modulators of proteasome dynamics.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to …

This study investigated modifications to the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart complications. db/db mice heart tissues were compared with WT mice tissues using RNA sequencing, qRT-PCR, and protein analysis to identify cardiac UPS modifications associated with diabetes. The findings unveiled a distinctive gene profile in the hearts of db/db mice with decreased levels of nppb mRNA and increased levels of Myh7, indicating potential cardiac dysfunction. The mRNA levels of USP18 (deubiquitinating enzyme), PSMB8, and PSMB9 (proteasome β-subunits) were down-regulated in db/db mice, while the mRNA levels of RNF167 (E3 ligase) were increased. Corresponding LMP2 and LMP7 proteins were down-regulated in db/db mice, and RNF167 was elevated in Adult diabetic mice. The reduced expression of LMP2 and LMP7, along with increased RNF167 expression, may contribute to the future cardiac deterioration commonly observed in diabetes. This study enhances our understanding of UPS imbalances in the hearts of diabetic mice and raises questions about the interplay between the UPS and other cellular processes, such as autophagy. Further exploration in this area could provide valuable insights into the mechanisms underlying diabetic heart complications and potential therapeutic targets.

Nuclear factor-ĸB (NF-ĸB) is an important transcriptional regulator of key cellular processes, including cell cycle, immune response, and malignant transformation. We found that the ubiquitin ligase Kip1 ubiquitination-promoting complex subunit 1 (KPC1; also known as Ring finger protein 123 – RNF123) stimulates ubiquitination and limited proteasomal processing of the p105 NF-ĸB precursor to generate p50, the active subunit of the heterodimeric transcription factor. KPC1 binds to the ankyrin repeats’ (AR) domain of NF-ĸB p105 via a short binding site of 7 amino acids—968-WILVRLW-974. Though mature NF-ĸB is overexpressed and constitutively active in different tumors, we found that overexpression of the p50 subunit, exerts a strong tumor suppressive effect. Furthermore, excess of KPC1 that stimulates generation of p50 from the p105 precursor, also results in a similar effect. Analysis of transcripts of …

Release Our Hostages Now! - PMC Back to Top Skip to main content NIH NLM Logo Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Rambam Maimonides Med J v.14(4); 2023 Oct PMC10619985 Other Formats PDF (248K) Actions Cite Collections Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Rambam Maimonides Med J v.14(4); 2023 Oct PMC10619985 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Logo of rmmj Rambam Maimonides Med J. 2023 Oct; 14(4): e0019. Published online 2023 Oct 29. doi: 10.5041/RMMJ.10507 …

Detection and classification of cells in immunohistochemistry (IHC) images play a vital role in modern computational pathology pipelines. Biopsy scoring and grading at the slide level is routinely performed by pathologists, but analysis at the cell level, often desired in personalized cancer treatment, is both impractical and non-comprehensive. With its remarkable success in natural images, deep learning is already the gold standard in computational pathology. Currently, some learning-based methods of biopsy analysis are performed at the tile level, thereby disregarding intra-tile cell variability; while others do focus on accurate cell segmentation, but do not address possible downstream tasks. Due to the shared low and high-level features in the tasks of cell detection and classification, these can be treated jointly using a single deep neural network, minimizing cumulative errors and improving the efficiency of both …

Aaron Ciechanover, MD, PhD, currently a Distinguished Research Professor in the Faculty of medicine at the Technion–Israel Institute of Technology in Haifa, Israel.

Targeting the protein-protein interactions involving CXCR4, a member of chemokine receptor family and G-protein-coupled receptor superfamily, has become an attractive therapeutic strategy for HIV-1 infection, hematopoietic stem cell mobilization, and cancer metastasis. As such, new small molecule CXCR4 antagonists are needed to offer therapeutic alternatives with enhanced clinical outcomes. Here, employing a fragment integrational approach we designed and synthesized a new and potent small molecule CXCR4 antagonist (named as HF51116), as well as a fluorescent (FITC)-labeled HF51116 (FITC-HF51116). HF51116 exhibited very high CXCR4 binding affinity with IC50 of 12 nM in competitive binding with a CXCR4 specific antibody 12G5, which is comparable to the wild type chemokines or synthetic peptides of much larger molecular sizes. Direct binding measurement using FITC-HF51116 further …

By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro, along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as β-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-β/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently …