Article
Multidisciplinary Sciences
Xiu Zhong, Huan Zeng, Zhiwei Zhou, Ya Su, Hang Cheng, Yanjie Hou, Yang She, Na Feng, Jia Wang, Feng Shao, Jingjin Ding
Summary: Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein, to trigger target cell pyroptosis. This study reveals the mechanism of how the Shigella flexneri ubiquitin-ligase virulence factor IpaH7.8 targets both GSDMB and GSDMD. The study also highlights the influence of different splicing isoforms of GSDMB on pyroptotic activity.
Review
Biochemistry & Molecular Biology
Emma I. Kane, Donald E. Spratt
Summary: Ankyrin repeat (AR) domains are the most common repetitive structure in eukaryotic proteins, mediating specific protein-protein interactions and recognizing a variety of intracellular substrates. Proteins with AR domains play crucial roles in biological processes and their dysfunction is linked to neurological diseases and disorders. Understanding the structure and mechanism of key AR-containing proteins can provide insights into how they support ubiquitylation and subsequent signaling pathways.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Vu Thuy Khanh Le-Trilling, Sofia Banchenko, Darius Paydar, Pia Madeleine Leipe, Lukas Binting, Simon Lauer, Andrea Graziadei, Robin Klingen, Christine Gotthold, Joerg Buerger, Thilo Bracht, Barbara Sitek, Robert Jan Lebbink, Anna Malyshkina, Thorsten Mielke, Juri Rappsilber, Christian M. T. Spahn, Sebastian Voigt, Mirko Trilling, David Schwefel
Summary: This study revealed that rat cytomegalovirus infection induces the loss of transcription factor STAT2, which is crucial for antiviral interferon signaling. It was found that viral protein E27 exploits the host-cell CRL4 complexes to degrade STAT2 through poly-ubiquitylation. Furthermore, structural analyses showed that E27 recruits STAT2 through a bipartite binding interface, partially overlapping with the IRF9 binding site.
Review
Chemistry, Multidisciplinary
Kristin M. Riching, Elizabeth A. Caine, Marjeta Urh, Danette L. Daniels
Summary: Targeted protein degradation is a crucial therapeutic approach that requires optimization of multiple parameters to achieve rapid degradation, high potency, and sustained target loss. Degradation is only the first milestone in degrader development, and understanding the dynamic cellular degradation profiles is essential for discovering effective therapeutic agents more efficiently.
CHEMICAL SOCIETY REVIEWS
(2022)
Article
Dermatology
Kathy Q. Cai, Caitlin Shellhamer, Tasuku Akiyama, Liselotte E. Jensen
Summary: The study reveals that Pellino1 plays crucial roles in restricting the replication and spread of HSV virus in the skin. Its deficiency leads to extensive viral dissemination and infection. The pathways involving Pellino1 may serve as novel therapeutic targets for patients with frequent or chronic HSV infections.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2023)
Review
Pharmacology & Pharmacy
Gregory R. Hughes, Ashley P. Dudey, Andrew M. Hemmings, Andrew Chantry
Summary: Targeting protein-protein interactions is a key focus in the development of small-molecule therapeutics. Despite challenges, there has been significant progress in utilizing the ubiquitin proteasome system for target-based degradation strategies.
DRUG DISCOVERY TODAY
(2021)
Review
Multidisciplinary Sciences
Roberta Sartori, Vanina Romanello, Marco Sandri
Summary: Skeletal muscle acts as a protein reservoir in the body and plays a key role in regulating glucose and lipid levels. The growth or loss of muscle mass can impact overall metabolism, movement, eating, and breathing. Various quality systems control muscle function, adapting cells to environmental and nutritional cues.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Veronika Kinterova, Jiri Kanka, Alexandra Bartkova, Tereza Toralova
Summary: SCF-dependent proteolysis, mediated by SCF (Skp1-Cullin 1-F-box) ligases, plays a crucial role in cell cycle regulation, DNA repair, and centrosome cycle. It is also important in oogenesis and embryogenesis, with SCF beta TrCP and SCFSEL-10/FBXW7 being the most studied ligases in these processes. However, there are still many SCF ligases involved in embryogenesis that need to be further elucidated.
Article
Multidisciplinary Sciences
Meng Zhang, Lin Lin, Chao Wang, Jinwei Zhu
Summary: Ephexin family guanine nucleotide exchange factors (GEFs) play critical roles in cellular processes, cancers, and brain disorders by transferring signals from Eph receptors to Rho GTPases. The study reveals that Ephexin4 utilizes both N- and C-terminal inhibitory modes for complete autoinhibition, which can be relieved through phosphorylation and PDZ protein binding, providing insights into the regulation of Ephexin4 GEF activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Rishith Ravindran, Anoop Kumar G. Velikkakath, Nikhil Dev Narendradev, Aneesh Chandrasekharan, T. R. Santhoshkumar, Srinivasa M. Srinivasula
Summary: This study reveals a novel role of endosomes in modulating upstream pathways of PRKN-dependent mitophagy initiation.
Article
Biochemistry & Molecular Biology
Zhigang Feng, Shanjia Ke, Chaoqun Wang, Shounan Lu, Yanan Xu, Hongjun Yu, Zihao Li, Bing Yin, Xinglong Li, Yongliang Hua, Baolin Qian, Miaoyu Bai, Yao Fu, Yingmei Zhang, Yaohua Wu, Yong Ma
Summary: This study investigated the role of E3 ubiquitin ligase Ring Finger Protein 125 (RNF125) in hepatocellular carcinoma (HCC). The results showed that RNF125 was downregulated in HCC tissues and its overexpression suppressed HCC proliferation and metastasis. Mechanistically, RNF125 accelerated the degradation of SRSF1 and inhibited the ERK signaling pathway. These findings suggest that RNF125 could be a potential therapeutic target for HCC.
Article
Biochemistry & Molecular Biology
Wenyan Yang, Shiqun Wang, Shengqiang Tong, Wei-Dong Zhang, Jiang-Jiang Qin
Summary: This article provides an overview of the ubiquitin-proteasome system (UPS) and its role in pancreatic cancer. Studies indicate that mutations or aberrant expression of UPS members can lead to rewriting of the ubiquitination code, affecting tumor growth, metastasis, immune evasion, and drug resistance. The article also reviews current UPS modulators and analyzes their potential as cancer therapies.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2024)
Review
Oncology
Chibuzo Sampson, Qiuping Wang, Wuxiyar Otkur, Haifeng Zhao, Yun Lu, Xiaolong Liu, Hai-long Piao
Summary: Ubiquitination, an important post-translational modification, is crucial for maintaining cellular protein homeostasis. E3 ubiquitin ligases are the most influential enzymes in the ubiquitination process and play a significant role in cancer hallmarks. The specificity of E3 ligases and their involvement in cancer hallmarks have led to the development of compounds that target them for cancer therapy. This review highlights the role of E3 ligases in cancer hallmarks and summarizes the application and significance of targeting E3 ligases as potential cancer therapy.
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Weaam Mohamed, Andreas D. Schenk, Georg Kempf, Simone Cavadini, Anja Basters, Alessandro Potenza, Wassim Abdul Rahman, Julius Rabl, Kurt Reichermeier, Nicolas H. Thomae
Summary: The study focuses on the structure and mechanism of the CRL4(DCAF1) ligase, identifying a novel mechanism by which unneddylated and substrate-free CUL4 ligases can be maintained in an inactive state.
Review
Biochemistry & Molecular Biology
Stephanie Diaz, Kankan Wang, Benita Sjogren, Xing Liu
Summary: Maintenance of protein homeostasis is crucial for eukaryotic biology, and the ubiquitin-proteasome system (UPS) plays an important role in the pathogenesis of cardiovascular diseases. Recent research has found that cullin-RING ubiquitin ligases (CRLs), an essential component of UPS, have significant physiological and pathological functions in the cardiovascular system.
Article
Biochemistry & Molecular Biology
Elton Zeqiraj, Lei Tian, Christopher A. Piggott, Monica C. Pillon, Nicole M. Duffy, Derek F. Ceccarelli, Alexander F. A. Keszei, Kristina Lorenzen, Igor Kurinov, Stephen Orlicky, Gerald D. Gish, Albert J. R. Heck, Alba Guarne, Roger A. Greenberg, Frank Sicheri
Article
Multidisciplinary Sciences
Alexander F. A. Keszei, Frank Sicheri
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2017)
Review
Biology
Danton H. O'Day, Alex Keszei
BIOLOGICAL REVIEWS
(2012)
Article
Biochemistry & Molecular Biology
Alexander F. A. Keszei, Xiaojing Tang, Craig McCormick, Elton Zeqiraj, John R. Rohde, Mike Tyers, Frank Sicheri
MOLECULAR AND CELLULAR BIOLOGY
(2014)
Article
Biochemistry & Molecular Biology
Matthew C. J. Yip, Alexander F. A. Keszei, Qing Feng, Vincent Chu, Michael J. McKenna, Sichen Shao
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2019)
Article
Biochemistry & Molecular Biology
Pankaj Garg, Derek F. Ceccarelli, Alexander F. A. Keszei, Igor Kurinov, Frank Sicheri, Sachdev S. Sidhu
JOURNAL OF MOLECULAR BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Brianna Lowey, Aaron T. Whiteley, Alexander F. A. Keszei, Benjamin R. Morehouse, Ian T. Mathews, Sadie P. Antine, Victor J. Cabrera, Dmitry Kashin, Percy Niemann, Mohit Jain, Frank Schwede, John J. Mekalanos, Sichen Shao, Amy S. Y. Lee, Philip J. Kranzusch
Article
Multidisciplinary Sciences
Benjamin R. Morehouse, Apurva A. Govande, Adi Millman, Alexander F. A. Keszei, Brianna Lowey, Gal Ofir, Sichen Shao, Rotem Sorek, Philip J. Kranzusch
Article
Chemistry, Multidisciplinary
Yumi Koga, Eileen M. Hoang, Yongho Park, Alexander F. A. Keszei, Jason Murray, Sichen Shao, Brian B. Liau
Summary: Cycloheximide (CHX) has been used for over half a century to study protein synthesis, but its rapid reversibility often leads to incomplete translation inhibition, prompting the need for improved reagents. The concise synthesis of C13-amide-functionalized CHX derivatives with increased potencies towards protein synthesis inhibition has been reported. These new compounds, particularly C13-aminobenzoyl CHX, have shown superior performance in ribosome profiling experiments, allowing for more effective capture of ribosome conformations.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Biochemistry & Molecular Biology
Nitzan Tal, Benjamin R. Morehouse, Adi Millman, Avigail Stokar-Avihail, Carmel Avraham, Taya Fedorenko, Erez Yirmiya, Ehud Herbst, Alexander Brandis, Tevie Mehlman, Yaara Oppenheimer-Shaanan, Alexander F. A. Keszei, Sichen Shao, Gil Amitai, Philip J. Kranzusch, Rotem Sorek
Summary: This study identifies the roles of cyclic pyrimidines cCMP and cUMP as immunity signaling molecules in bacterial defense against viruses. A family of bacterial pyrimidine cyclase enzymes was discovered to specifically synthesize these molecules following phage infection, activating immune effectors for antiviral response. Defense systems encoding pyrimidine cyclases, known as Pycsar, are widespread in prokaryotes, providing a clear biological function for cCMP and cUMP in bacterial immunity.
Article
Biochemistry & Molecular Biology
Alexander F. A. Keszei, Matthew C. J. Yip, Ta-Chien Hsieh, Sichen Shao
Summary: Cryo-EM structures of the cytosolic metazoan GET complex targeting nascent tail-anchored membrane proteins to the endoplasmic reticulum reveal interactions that coordinate client transfer between two protein chaperones.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Benjamin R. Morehouse, Matthew C. J. Yip, Alexander F. A. Keszei, Nora K. McNamara-Bordewick, Sichen Shao, Philip J. Kranzusch
Summary: The study reveals that the activation of STING protein requires the formation of a filament structure, which is crucial in antiviral defense in animals and prokaryotes. The mechanism involves the exposure of STING interfaces and the binding of repeating dimeric units. These findings provide important insights into prokaryotic antiviral signaling.