Review
Biochemistry & Molecular Biology
Vandita Dwivedi, Karina Yaniv, Michal Sharon
Summary: Evidence from clinical studies show that functional 20S proteasome complexes circulate in plasma, with elevated levels in patients with various diseases. The levels of circulating c20S correlate positively with treatment efficacy and survival rates, indicating a potential role in pathophysiology.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Plant Sciences
Peifeng Yu, Zhihua Hua
Summary: Functional studies of the ubiquitin-26S proteasome system (UPS) have revealed its involvement in various aspects of plant life. However, the specific role of UPS in development, particularly in seeds and fruits, remains to be fully understood. Our research demonstrates the interaction between proteasome and autophagy and highlights their regulatory role in proteome homeostasis during early silique and/or seed development.
Article
Multidisciplinary Sciences
Donghoon Lee, Alfred L. Goldberg
Summary: Heat shock induces protein unfolding, leading to increased activity of proteasomes and degradation of ubiquitinated proteins. This response helps cells clear damaged proteins and maintain cellular homeostasis under proteotoxic stress conditions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Richard S. Marshall, Richard D. Vierstra
Summary: Proteasomes, as central effectors of ubiquitin-mediated proteolysis, are regulated by multiple levels including proteaphagy, a mechanism that degrades unwanted or dysfunctional particles via autophagy. This study demonstrated the importance of ubiquitylation driven by the trio of Ub ligases (E3s), San1, Rsp5, and Hul5, in promoting nuclear export and recognition by the autophagy receptor Cue5. The study also highlighted the assembly of topologically complex Ub chains on the regulatory particle, allowing for the generation of autophagy-competent substrates. Overall, proteaphagy appears to be a fundamental mechanism for eliminating inactive or misfolded proteins.
Article
Chemistry, Multidisciplinary
Rupam Ghosh, Yiling Xiao, Jaka Kragelj, Kendra K. Frederick
Summary: NMR combined with DNP enhances sensitivity and resolution for detecting proteins, but sensitivity gains are influenced by experimental conditions and sample composition, leading to uncertainty about cellular sample integrity.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Review
Microbiology
Hao Zhang, Gang Lin
Summary: Proteasomes are ATP-dependent, N-terminal nucleophile hydrolases that are essential for intracellular protein turnover and present in all biological kingdoms. Inhibiting proteasomes can be harmful to cell viability, but proteasome inhibitor drugs have revolutionized the treatment of multiple myeloma. Efforts are being made to develop inhibitors selective for microbial proteasomes, with promising progress in targeting pathogenic microbes for diseases like leishmaniasis and Chagas disease.
Article
Chemistry, Multidisciplinary
Dacheng Ma, Qichen Yuan, Fei Peng, Victor Paredes, Hongzhi Zeng, Emmanuel C. Osikpa, Qiaochu Yang, Advaith Peddi, Anika Patel, Megan S. Liu, Zheng Sun, Xue Gao
Summary: This study developed a scalable chemically inducible dimerization platform (PROTAC-CID) based on proteolysis-targeting chimera, which enables inducible gene regulation and gene editing. It can fine-tune gene expression at gradient levels or multiplex biological signals. By coupling it with genetic circuits, digitally inducible expression of DNA recombinases and base-and prime-editors for transient genome manipulation are achieved. Furthermore, a compact PROTAC-CID system is packaged into adeno-associated viral vectors for inducible and reversible gene activation in vivo. This work provides a versatile molecular toolbox for chemically inducible gene regulation in human cells and mice.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biology
Willa Wen-You Yim, Hayashi Yamamoto, Noboru Mizushima
Summary: Monitoring autophagic flux is crucial for autophagy studies. Current assays for mammalian cells are complicated and yield less accurate results. This paper presents a HaloTag-based processing assay to monitor autophagic flux in mammalian cells, which provides a simple and effective method for precise measurement.
Article
Multidisciplinary Sciences
Rocio A. Barahona, Samuel Morabito, Vivek Swarup, Kim N. Green
Summary: Microglia play a role in the regulation of perineuronal nets (PNNs) but not in the maintenance of diurnal rhythms.
SCIENTIFIC REPORTS
(2022)
Editorial Material
Biochemistry & Molecular Biology
Xiang Chen, Kylie J. Walters
Summary: The study by de Almeida et al. (2021) describes the development of a temporally controlled CRISPR-Cas9 screen for identifying mechanisms that control MYC levels. They discovered that intact proteasomes are imported into the nucleus through the binding of AKIRIN2 to proteasomes at one end and a nuclear import receptor at the other.
Review
Biochemistry & Molecular Biology
Dare E. George, Jetze J. Tepe
Summary: The proteasome system is crucial for protein degradation, and dysfunction can lead to various diseases. Enhancing proteasome-mediated protein degradation with small molecules may be a valuable strategy for treating neurodegenerative diseases.
Review
Biochemistry & Molecular Biology
Won Hoon Choi, Sumin Kim, Seoyoung Park, Min Jae Lee
Summary: This article summarizes the importance of extracellular proteasomes (c-proteasomes), pointing out their role in extracellular proteostasis, as well as the characteristics and potential pathological significance of c-proteasomes.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Hind Atta, Nouran Alzahaby, Nadia M. Hamdy, Soha H. Emam, Amr Sonousi, Laila Ziko
Summary: This article discusses the degradation mechanism, localization, and diagnostic/prognostic applications of the 20S proteasome. It also summarizes the FDA-approved proteasome inhibitors and their limited efficacy in solid tumors, as well as resistance mechanisms. Furthermore, it explores the future prospects for developing new proteasome inhibitors for the treatment of solid tumors.
BIOORGANIC CHEMISTRY
(2023)
Article
Biology
Ginto George, Satoshi Ninagawa, Hirokazu Yagi, Jun-ichi Furukawa, Noritaka Hashii, Akiko Ishii-Watabe, Ying Deng, Kazutoshi Matsushita, Tokiro Ishikawa, Yugoviandi P. Mamahit, Yuta Maki, Yasuhiro Kajihara, Koichi Kato, Tetsuya Okada, Kazutoshi Mori
Summary: The sequential mannose trimming process in N-glycan modification involves EDEM2, EDEM3, and EDEM1 at different stages, with each enzyme playing a specific role in the endoplasmic reticulum-associated degradation of misfolded glycoproteins. The study establishes the entire route of oligosaccharide processing and confirms the Golgi localization of MAN1B, highlighting the essential enzymes involved in glycoprotein ERAD.
Article
Biochemistry & Molecular Biology
Jennifer L. Warnock, Gabriel W. Jobin, Sandhya Kumar, Robert J. Tomko
Summary: The 26S proteasome is a protease that degrades unneeded or defective proteins in eukaryotes. The chaperone Nas6 can promote the dissociation of mature proteasomes into regulatory particle (RP) and core particle (CP) in cells with defects on either side of the RP-CP interface. This function of Nas6 may play a quality control role by promoting the recycling of functional subcomplexes in defective proteasomes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biology
Osamu Nakabayashi, Hirotaka Takahashi, Kenta Moriwaki, Sachiko Komazawa-Sakon, Fumiaki Ohtake, Shin Murai, Yuichi Tsuchiya, Yuki Koyahara, Yasushi Saeki, Yukiko Yoshida, Soh Yamazaki, Fuminori Tokunaga, Tatsuya Sawasaki, Hiroyasu Nakano
Summary: The E3 ligase MIB2 ubiquitylates apoptosis-inhibitor cFLIP, suppressing RIPK1 kinase activity-dependent and -independent apoptosis. Deletion of MIB2 enhances RIPK1 kinase activity and impairs ubiquitylation of cFLIP(L), resulting in increased apoptosis.
COMMUNICATIONS BIOLOGY
(2021)
Article
Genetics & Heredity
Sarah K. Gersing, Yong Wang, Martin Gronbaek-Thygesen, Caroline Kampmeyer, Lene Clausen, Martin Willemoes, Claes Andreasson, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Canavan disease is a severe neurodegenerative disorder genetically linked to the ASPA gene. The ASPA C152W variant undergoes increased proteasomal degradation due to interference with the de novo folding pathway, although its native structure is largely preserved. Quality control components like Hsp70 and Hsp110 play key roles in the degradation of ASPA C152W, suggesting potential therapeutic targets for protein misfolding diseases.
Article
Biochemistry & Molecular Biology
Sarah F. Ruidiaz, Jesper E. Dreier, Rasmus Hartmann-Petersen, Birthe B. Kragelund
Summary: Two IDPs, DSS1 and CSNAP, have differences in structure and function, with even subtle sequence variance potentially leading to different functional traits. These traits may impact their ability to engage in multiple interactions, thus affecting their interactome sizes.
Article
Biochemistry & Molecular Biology
Takumi Tsunoda, Miho Riku, Norika Yamada, Hikaru Tsuchiya, Takuya Tomita, Minako Suzuki, Mari Kizuki, Akihito Inoko, Hideaki Ito, Kenta Murotani, Hideki Murakami, Yasushi Saeki, Kenji Kasai
Summary: HECT-type ubiquitin E3 ligases, such as ITCH, play important roles in cellular functions by ubiquitinating various substrates. FAM189A2, a downregulated gene in breast cancer, acts as a unique activator for ITCH to regulate CXCR4 activity in endosomes, influencing chemotaxis and mammosphere formation of breast cancer cells.
Article
Biochemistry & Molecular Biology
Yoshino Akizuki, Mai Morita, Yuki Mori, Ai Kaiho-Soma, Shivani Dixit, Akinori Endo, Marie Shimogawa, Gosuke Hayashi, Mikihiko Naito, Akimitsu Okamoto, Keiji Tanaka, Yasushi Saeki, Fumiaki Ohtake
Summary: Targeted protein degradation through chemical hijacking of E3 ubiquitin ligases is a new concept in precision medicine. This study reveals the importance of K63-linked ubiquitin chains and UBE2N in degrader-induced proteasomal degradation and demonstrates the diversity of the ubiquitin code used for chemical hijacking.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mette Ahrensback Roesgaard, Jeppe E. Lundsgaard, Estella A. Newcombe, Nina L. Jacobsen, Francesco Pesce, Emil E. Tranchant, Soren Lindemose, Andreas Prestel, Rasmus Hartmann-Petersen, Kresten Lindorff-Larsen, Birthe B. Kragelund
Summary: By comparing the effects of aspartate and glutamates in intrinsically disordered proteins, the study found that while the variants support similar function and global dimensions, they differ in binding affinities and population of local transient structural elements, indicating potential roles in functional diversity.
Review
Oncology
Amanda B. Abildgaard, Sofie Nielsen, Inge Bernstein, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Accurate diagnosis and clinical interpretation of individual variants are crucial for the treatment of Lynch syndrome, a heritable cancer disease. Traditional protein variant classification methods are complex, but recent developments in high-throughput technologies and computational prediction tools offer new possibilities for assessing variants of unknown significance and gaining mechanistic insights into the disease.
BRITISH JOURNAL OF CANCER
(2023)
Review
Biochemistry & Molecular Biology
Estella A. Newcombe, Elise Delaforge, Rasmus Hartmann-Petersen, Karen Skriver, Birthe B. Kragelund
Summary: Phosphorylation is the most common post-translational modification in eukaryotes, particularly in intrinsically disordered proteins. The addition of a single phosphoryl group to a disordered chain can dramatically impact its function. Multiple phosphorylation sites in IDPs result in increased complexity and novel mechanisms. Understanding the effects of IDP phosphorylation is crucial in disease research and studying other PTMs.
ESSAYS IN BIOCHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Bayan Mashahreh, Shir Armony, Kristoffer Ene Johansson, Alon Chappleboim, Nir Friedman, Richard G. Gardner, Rasmus Hartmann-Petersen, Kresten Lindorff-Larsen, Tommer Ravid
Summary: This study identifies a large cohort of proteome-derived degrons through an unbiased peptidome stability screen in yeast and establishes constraints governing degron potency. The results suggest that degrons with transmembrane domain-like characteristics are the most probable sequences to act as key quality control determinants.
NATURE COMMUNICATIONS
(2022)
Article
Microbiology
Hirohito Ishigaki, Fumihiko Yasui, Misako Nakayama, Akinori Endo, Naoki Yamamoto, Kenzaburo Yamaji, Cong Thanh Nguyen, Yoshinori Kitagawa, Takahiro Sanada, Tomoko Honda, Tsubasa Munakata, Masahiko Higa, Sakiko Toyama, Risa Kono, Asako Takagi, Yusuke Matsumoto, Aya Koseki, Kaori Hayashi, Masanori Shiohara, Koji Ishii, Yasushi Saeki, Yasushi Itoh, Michinori Kohara
Summary: The rDIs-S vaccine, developed using the attenuated vaccinia virus Dairen-I (DIs) strain platform carrying the SARS-CoV-2 S gene, has shown broad and durable protective immunity against various strains of SARS-CoV-2 in animal and mouse models. Proteomic analysis revealed that the vaccine can prevent and restore protein expression related to the pathogenic effects and immune response of SARS-CoV-2 infection. Long-term studies also demonstrated that vaccination with rDIs-S maintains S protein-specific antibody titers for at least 6 months.
FRONTIERS IN MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Fia B. Larsen, Matteo Cagiada, Jonas Dideriksen, Amelie Stein, Kresten Lindorff-Larsen, Rasmus Hartmann-Petersen
Summary: Catechol-O-methyltransferase (COMT) is an important enzyme involved in the metabolism of neurotransmitters and catecholamine drugs, and its variation can affect pharmacokinetics and drug availability.
Article
Biochemistry & Molecular Biology
Caroline Kampmeyer, Martin Gronbaek-Thygesen, Nicole Oelerich, Michael H. Tatham, Matteo Cagiada, Kresten Lindorff-Larsen, Wouter Boomsma, Kay Hofmann, Rasmus Hartmann-Petersen
Summary: Lysine is a common amino acid in the human proteome, but there are proteins that lack lysine residues. These lysine deserts are common in intrinsically disordered proteins involved in the ubiquitin-proteasome system. Introducing lysine residues can increase ubiquitylation of these proteins, and their stability and function may be affected. This avoidance of lysine residues may be an evolutionary mechanism to prevent unnecessary ubiquitylation in proteins closely involved with the ubiquitylation machinery.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Nina L. Jacobsen, Magnus Bloch, Peter S. Millard, Sarah F. Ruidiaz, Jonas D. Elsborg, Wouter Boomsma, Ruth Hendus-Altenburger, Rasmus Hartmann-Petersen, Birthe B. Kragelund
Summary: This study found that Schizosaccharomyces pombe Dss1 is phosphorylated by casein kinase 2 at three threonine sites in its linker region. The phosphorylation does not affect its ubiquitin binding ability, but slightly destabilizes the C-terminal alpha-helix and directly interacts with the forkhead-associated domain of the RING-FHA E3-ubiquitin ligase defective in mitosis 1 (Dma1). These phosphorylation sites are absent in human Dss1.
Article
Multidisciplinary Sciences
Matteo Cagiada, Sandro Bottaro, Soren Lindemose, Signe M. Schenstrom, Amelie Stein, Rasmus Hartmann-Petersen, Kresten Lindorff-Larsen
Summary: The authors propose a machine-learning based method to predict functional sites in proteins by combining sequence and structural information. Proteins play important roles in biology, biotechnology, and pharmacology, and missense variants can cause disease. Discovering functional sites in proteins is challenging due to the lack of comprehensive data sets.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Yoko Hasegawa, Thais Huarancca Reyes, Tomohiro Uemura, Anirban Baral, Akari Fujimaki, Yongming Luo, Yoshie Morita, Yasushi Saeki, Shugo Maekawa, Shigetaka Yasuda, Koki Mukuta, Yoichiro Fukao, Keiji Tanaka, Akihiko Nakano, Junpei Takagi, Rishikesh P. Bhalerao, Junji Yamaguchi, Takeo Sato
Summary: This study identified the interaction between the trans-Golgi network/early endosome localized SNARE protein SYP61 and the transmembrane ubiquitin ligase ATL31 in Arabidopsis. It also revealed the critical role of SYP61 in plant responses to nutrient stress, as well as its ubiquitination under low carbon/high nitrogen conditions. These findings provide important insights into the ubiquitin signaling and membrane trafficking machinery in plants.