Editorial Material
Biochemistry & Molecular Biology
Yuan Xie, Minglei Zhao
Summary: Proper regulation of protein degradation is crucial for cell physiology. In the recent issue of Cell, Baek et al. revealed the assembly and disassembly mechanism of a widely present ubiquitin ligase class called CRL, through a key regulatory protein, CAND1.
Article
Multidisciplinary Sciences
Jie Li, Gregory J. Krause, Qi Gui, Susmita Kaushik, Gergely Rona, Qingyue Zhang, Feng-Xia Liang, Avantika Dhabaria, Carlos Anerillas, Jennifer L. Martindale, Nikita Vasilyev, Manor Askenazi, Beatrix Ueberheide, Evgeny Nudler, Myriam Gorospe, Ana Maria Cuervo, Michele Pagano
Summary: This study identifies a new function for mammalian SKP1 in the endolysosomes, which is independent of its established role as a component of ubiquitin ligases. SKP1 is found to be phosphorylated under nutrient-poor conditions, promoting V-ATPase assembly and acidification of late endosomes for degradation. Under nutrient-rich conditions, phosphorylated SKP1 is SUMOylated and allows unconventional secretion through interaction with SEC22B.
Article
Multidisciplinary Sciences
Dawadschargal Dubiel, Jing Wang, Roland Hartig, Supattra Chaithongyot, Wolfgang Daniel, Michael Naumann
Summary: The COP9 signalosome and cullin-RING ubiquitin ligases form latent CSN-CRL complexes detectable in cells. CSN7A and CSN7B variants preferentially bind to CRL3 and CRL4A/B, respectively. Specific cellular functions require latent CSN7A-CRL3 and CSN7B-CRL4A/B particles, with curcumin-induced cell death requiring latent CSN7B-CRL4A.
Article
Biochemistry & Molecular Biology
MuChun Tsai, Wissam Osman, Jessica Adair, Rabab ElMergawy, Lexie Chafin, Finny Johns, Daniela Farkas, Ajit Elhance, James Londino, Rama K. Mallampalli, George DeMartino
Summary: This study revealed that IFNLR1 protein is rapidly degraded after influenza infection, and FBXO45 mediates the polyubiquitination and degradation of IFNLR1 protein. Additionally, the expression and silencing of FBXO45 differentially regulate the stability of IFNLR1 protein and the expression of interferon-stimulated genes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Benoit Pelletier, Stephanie Duhamel, Guillaume Tambutet, Scott Jarvis, Patrick Cleroux, Maud David, Pierre-Luc Tanguay, Laure Voisin, Clint James, Rico Lavoie, Yves Gareau, Joel Flynn-Robitaille, Thierry Lorca, Rejean Ruel, Anne Marinier, Sylvain Meloche
Summary: p21Cip1 is a CDK inhibitor that can halt cell proliferation and tumor growth. However, its expression is often decreased in cancer cells due to the loss of transcriptional activators or increased protein degradation. In this study, a benzodiazepine series of molecules was identified as inhibitors of p21 degradation. Further analysis revealed that UBCH10, a ubiquitin-conjugating enzyme, serves as a cellular target of the benzodiazepine series. Moreover, an optimized benzodiazepine analogue was found to inhibit UBCH10 activity and prevent substrate proteolysis.
ACS CHEMICAL BIOLOGY
(2023)
Article
Cell Biology
Tamara Moretti, Kyungho Kim, Astha Tuladhar, Jinoh Kim
Summary: CUL3-RING ubiquitin ligases (CRL3s) play a crucial role in various cellular processes through different BTB-domain proteins. KLHL12, a BTB-domain protein, is involved in the export of large cargo molecules, such as procollagen, from the endoplasmic reticulum (ER). CRL3KLHL12 monoubiquitylates SEC31, leading to increased size of COPII vesicles and facilitating procollagen secretion.
MOLECULAR BIOLOGY OF THE CELL
(2023)
Article
Biochemistry & Molecular Biology
Jae Ho Kim, Woo Joo Jung, Moon Seok Kim, Yong Weon Seo
Summary: TaF-box3, an F-box gene from wheat, is involved in the regulation of plant flowering time and is regulated by endogenous and exogenous signals. Overexpression of TaF-box3 in Arabidopsis leads to early flowering and altered leaf cell size. It was found that TaF-box3 overexpression decreases the transcript level of a flowering time-related gene and reduces the trimethylation of histone H3K4 and H3K36. ChIP experiments confirmed that TaF-box3 is involved in demethylating FLC chromatin, thereby regulating flowering time in Arabidopsis.
Article
Oncology
Haiyun Wang, Qiuling Huang, Jianhong Xia, Shan Cheng, Duanqing Pei, Xiaofei Zhang, Xiaodong Shu
Summary: MIB1 overexpression is detected in lung squamous carcinoma and adenocarcinoma and negatively correlates with patient survival. MIB1 induces EMT and cell migration through the Notch pathway, and degrades NRF2 in a Notch-independent manner, disrupting cellular antioxidant capacity.
MOLECULAR CANCER RESEARCH
(2022)
Article
Cell Biology
Jiansong Liu, Yichen Zang, Cunying Ma, Dandan Wang, Zhuangfei Tian, Xia Xu, Wenjuan Li, Jihui Jia, Zhifang Liu
Summary: This study reveals that STYX acts as an oncogene in gastric cancer (GC) by inhibiting the degradation function of FBXO31, and may serve as a potential therapeutic target and prognostic biomarker in GC. STYX's interaction with FBXO31 and its regulation by c-Jun and Helicobacter pylori are key mechanisms driving GC progression.
CELL DEATH & DISEASE
(2022)
Article
Plant Sciences
Maria Cecilia Terrile, Nuria Malena Tebez, Silvana Lorena Colman, Julieta Lisa Mateos, Esperanza Morato-Lopez, Nuria Sanchez-Lopez, Alicia Izquierdo-Alvarez, Anabel Marina, Luz Irina A. Calderon Villalobos, Mark Estelle, Antonio Martinez-Ruiz, Diego Fernando Fiol, Claudia Anahi Casalongue, Maria Jose Iglesias
Summary: E3 ubiquitin ligases are crucial in plant biology and play a key role in the perception and signaling of hormones. The redox modification of proteins through S-nitrosation serves as an important regulatory mechanism in hormonal signaling pathways. This study confirmed the S-nitrosation of TIR1 and COI1, highlighting the functional relevance of this modification in the response to auxins and jasmonates.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Hyun Mi Kang, Dae Hun Kim, Mijin Kim, Yoohong Min, Bohyeon Jeong, Kyung Hee Noh, Da Yong Lee, Hyun-Soo Cho, Nam-Soon Kim, Cho-Rok Jung, Jung Hwa Lim
Summary: This study discovered that the FBXL17-SPAST pathway is involved in the pathogenicity of hereditary spastic paraplegia (HSP) through loss of function and quantitative regulation. Targeting FBXL17 could provide new insights into HSP therapeutics.
CELL AND BIOSCIENCE
(2022)
Article
Cell Biology
Jing Wang, Dawadschargal Dubiel, Yanmeng Wu, Yabin Cheng, Dieter A. Wolf, Wolfgang Dubiel
Summary: CSN7A and CSN7B have overlapping functions in deneddylation, but CSN7B plays a unique role in DNA damage sensing and affects DNA repair pathway choice; knockout of CSN7B leads to resistance to DNA damage and a switch in DNA repair pathway.
Article
Multidisciplinary Sciences
Debasish Paul, Stephen C. Kales, James A. Cornwell, Marwa M. Afifi, Ganesha Rai, Alexey Zakharov, Anton Simeonov, Steven D. Cappell
Summary: The authors develop a fluorescent biosensor to monitor beta-TrCP activity in live cells and find that beta-TrCP remains constitutively active throughout the cell cycle. They also identify receptor-tyrosine kinase signaling as a key regulator of beta-TrCP activity.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Eric Schulze-Niemand, Michael Naumann
Summary: The COP9 signalosome (CSN) is a universal regulator of Cullin-RING ubiquitin ligases (CRLs) that control cellular processes by degrading signaling proteins. The CSN, with its eight-subunit architecture, inactivates CRLs by removing a small ubiquitin-like modifier called Nedd8. Recent findings on the versatile regulation of CSN-CRL complexes are presented in this review.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Sachiho Taniguchi, Yuji Ono, Yukako Doi, Shogo Taniguchi, Yuta Matsuura, Ayuka Iwasaki, Noriaki Hirata, Ryosuke Fukuda, Keitaro Inoue, Miho Yamaguchi, Anju Tashiro, Daichi Egami, Shunsuke Aoki, Yasumitsu Kondoh, Kaori Honda, Hiroyuki Osada, Hiroyuki Kumeta, Tomohide Saio, Tsukasa Okiyoneda
Summary: RFFL is a highly expressed apoptotic inhibitor in cancers, and its inhibition suppresses cancer cell growth and enhances chemotherapy sensitivity. It has been discovered that α-tocopherol succinate (alpha TOS) can act as a ligand for RFFL, inhibiting the RFFL-substrate interaction and increasing the cell surface expression of CFTR channel, which may have therapeutic potential for both cancer and cystic fibrosis.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Cell Biology
Chihiro Sakaguchi, Kazuya Ichihara, Akihiro Nita, Yuta Katayama, Keiichi Nakayama
Summary: The CHD4 protein is a chromatin remodeling factor that interacts with various proteins to regulate cellular activities. In this study, LCORL and NOL4L were identified as new interactors of CHD4, suggesting their potential role in suppressing the Notch signaling pathway in mammalian cells.
Article
Multidisciplinary Sciences
Mitsuaki Fujimoto, Ryosuke Takii, Masaki Matsumoto, Mariko Okada, Keiich I. Nakayama, Ryuichiro Nakato, Katsunori Fujiki, Katsuhiko Shirahige, Akira Nakai
Summary: The study shows that phosphorylation of HSF1 during heat shock recruits histone acetyltransferases and histone acetylation reader proteins TRIM33 and TRIM24 to the HSP72 promoter, leading to histone H2B mono-ubiquitination, promoting the establishment of an active chromatin status, and affecting melanoma cell proliferation.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Hideyuki Shimizu, Manabu Kodama, Masaki Matsumoto, Yasuko Orba, Michihito Sasaki, Akihiko Sato, Hirofumi Sawa, Keiichi Nakayama
Summary: In this study, a graph-based deep learning approach called LIGHTHOUSE was developed to discover the hidden principles underlying the association of small-molecule compounds with target proteins. LIGHTHOUSE estimated protein-compound scores without relying on 3D structural information, incorporating known evolutionary relations and available experimental data. It successfully identified therapeutics for various diseases and predicted ethoxzolamide as a therapeutic for COVID-19, which was proven effective against different variants of SARS-CoV-2.
Article
Developmental Biology
Anna Lozano-Urena, Laura Lazaro-Carot, Esteban Jimenez-Villalba, Raquel Montalban-Loro, Isabel Mateos-White, Pere Duart-Abadia, Irene Martinez-Gurrea, Keiichi I. Nakayama, Isabel Farinas, Martina Kirstein, Cristina Gil-Sanz, Sacri R. Ferron
Summary: Adult neurogenesis relies on multipotent neural stem cells (NSCs) with unique properties and growth requirements. Although many imprinted genes' roles in adult neurogenesis are still unknown, insulin-like growth factor 2 (IGF2) has been shown to contribute to NSC maintenance and promote terminal differentiation into astrocytes, neurons, and oligodendrocytes. This differentiation effect is mediated by the expression of the maternally expressed gene Cdkn1c, encoding the cell cycle inhibitor p57, and occurs independently of its role in cell-cycle progression, balancing the relationship between astrogliogenesis, neurogenesis, and oligodendrogenesis.
Article
Biochemistry & Molecular Biology
Reona Wada, Shun Fujinuma, Hirokazu Nakatsumi, Masaki Matsumoto, Keiichi Nakayama
Summary: Mechanistic target of rapamycin complex 1 (mTORC1) is a serine-threonine kinase activated by extracellular signals, regulating various biological processes. PBX2 was identified as a novel target dephosphorylated downstream of mTORC1. The phosphorylation of PBX2 is regulated by the antagonistic actions of glycogen synthase kinase 3 (GSK3) and protein phosphatase 1 (PP1).
JOURNAL OF BIOCHEMISTRY
(2023)
Article
Oncology
Akihiro Kitagawa, Tsuyoshi Osawa, Miwa Noda, Yuta Kobayashi, Sho Aki, Yusuke Nakano, Tomoko Saito, Dai Shimizu, Hisateru Komatsu, Maki Sugaya, Junichi Takahashi, Keisuke Kosai, Seiichiro Takao, Yushi Motomura, Kuniaki Sato, Qingjiang Hu, Atsushi Fujii, Hiroaki Wakiyama, Taro Tobo, Hiroki Uchida, Keishi Sugimachi, Kohei Shibata, Tohru Utsunomiya, Shogo Kobayashi, Hideshi Ishii, Takanori Hasegawa, Takaaki Masuda, Yusuke Matsui, Atsushi Niida, Tomoyoshi Soga, Yutaka Suzuki, Satoru Miyano, Hiroyuki Aburatani, Yuichiro Doki, Hidetoshi Eguchi, Masaki Mori, Keiichi I. Nakayama, Teppei Shimamura, Tatsuhiro Shibata, Koshi Mimori
Summary: This study analyzed the genomic, transcriptomic, proteomic, and metabolomic profiles of intrahepatic cholangiocarcinoma (ICC) samples, revealing the presence of multiple genomic alterations and metabolic pathway changes. The identified ICC-specific metabolic pathway could potentially be targeted for new therapeutic interventions.
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Takeru Oka, Tsunaki Higa, Osamu Sugahara, Daisuke Koga, Shogo Nakayama, Keiichi I. Nakayama
Summary: This study established a syngeneic orthotopic transplantation model in mice based on intestinal cancer organoids, and revealed that quiescent p57(+) CSCs play a significant role in cancer relapse and are resistant to chemotherapy. Ablation of p57(+) CSCs suppressed tumor regrowth after chemotherapy, suggesting p57(+) CSCs as a promising therapeutic target for malignant intestinal cancer.
Article
Biochemistry & Molecular Biology
Yuki Kito, Akinobu Matsumoto, Kazuya Ichihara, Chisa Shiraishi, Ronghao Tang, Atsushi Hatano, Masaki Matsumoto, Peixun Han, Shintaro Iwasaki, Keiichi Nakayama
Summary: Translation begins with the binding of the eIF4F complex to the 5' mRNA cap, followed by scanning ribosomes searching for the start codon in the 5' untranslated region. This study shows that the ASC-1 complex (ASCC) associates with scanning ribosomes to regulate translation initiation. Knockdown of ASCC3, a subunit of ASCC, impairs the loading and scanning dynamics of the 43S preinitiation complex, leading to reduced translation efficiency. These findings demonstrate that ASCC not only promotes dissociation of colliding 80S ribosomes but also facilitates efficient translation initiation by scanning ribosomes.
Article
Multidisciplinary Sciences
Katsuhiko Takahashi, Hitoshi Amano, Tomohiko Urano, Minqi Li, Meiko Oki, Kazuhiro Aoki, Norio Amizuka, Keiichi I. Nakayama, Keiko Nakayama, Nobuyuki Udagawa, Nobuaki Higashi
Summary: The study found that p57(Kip2) plays an important role in bone development and is associated with the vitamin D receptor (VDR). 1,25-(OH)(2)VD3 can promote the differentiation of osteoblasts by regulating p57(Kip2), and simultaneously reduce the generation of osteoclasts.
Article
Multidisciplinary Sciences
Chisa Shiraishi, Akinobu Matsumoto, Kazuya Ichihara, Taishi Yamamoto, Takeshi Yokoyama, Taisuke Mizoo, Atsushi Hatano, Masaki Matsumoto, Yoshikazu Tanaka, Eriko Matsuura-Suzuki, Shintaro Iwasaki, Shouji Matsushima, Hiroyuki Tsutsui, Keiichi I. Nakayama
Summary: This study reveals that the RPL3L-encoded ribosomal protein specifically expressed in heart and skeletal muscle affects translation elongation dynamics, and its deficiency impairs cardiac contractility in mice. The results provide insights into the mechanisms and physiological relevance of tissue-specific translational regulation.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Shun Fujinuma, Hirokazu Nakatsumi, Hideyuki Shimizu, Shigeaki Sugiyama, Akihito Harada, Takeshi Goya, Masatake Tanaka, Motoyuki Kohjima, Masatomo Takahashi, Yoshihiro Izumi, Mikako Yagi, Dongchon Kang, Mari Kaneko, Mayo Shigeta, Takeshi Bamba, Yasuyuki Ohkawa, Keiichi I. Nakayama
Summary: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder that can lead to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The transcription factor FOXK1 plays a key role in hepatic lipid metabolism by suppressing lipid catabolism. Inhibition of FOXK1 has shown promising results in improving hepatic steatosis, inflammation, fibrosis, and tumorigenesis, making it a potential therapeutic strategy for NAFLD-NASH and HCC.
Article
Multidisciplinary Sciences
Kanae Yumimoto, Shigeaki Sugiyama, Saori Motomura, Daisuke Takahashi, Keiichi I. Nakayama
Summary: ROS poses a risk for the transition of vertebrates from aquatic to terrestrial life, and how ancestral organisms adapted to such ROS exposure has remained a mystery. By studying the evolution of Keap1 gene, researchers found that the duplication of Keap1 gene in fish and the lower affinity of Keap1B for Cul3 contributed to robust Nrf2 induction in response to ROS exposure. Mutation of mammalian Keap1 to resemble zebrafish Keap1A resulted in an attenuated Nrf2 response and increased sensitivity to ultraviolet radiation. These findings suggest that the molecular evolution of Keap1 was essential for adaptation to terrestrial life.
Article
Multidisciplinary Sciences
Shintaro Funasaki, Atsushi Hatano, Hirokazu Nakatsumi, Daisuke Koga, Osamu Sugahara, Kanae Yumimoto, Masaya Baba, Masaki Matsumoto, Keiichi I. Nakayama
Summary: CD4(+)CD8(+) double-positive (DP) thymocytes undergo positive or negative selection based on the strength of TCR stimulation. Phosphoproteome analysis revealed that high-affinity peptide ligands induce phosphorylation of p90 ribosomal protein kinase (RSK) at Thr562. This phosphorylation triggers RSK translocation to the nucleus, where it phosphorylates the nuclear receptor Nur77, promoting its mitochondrial translocation for apoptosis induction.
Article
Biochemistry & Molecular Biology
Shigeaki Sugiyama, Kanae Yumimoto, Shun Fujinuma, Keiichi Nakayama
Summary: This study compared 10 CCR2 antagonists and found that MK0812 is the most potent inhibitor. It also demonstrated the efficacy of MK0812 in reducing lung metastasis in a mouse model.
JOURNAL OF BIOCHEMISTRY
(2023)
Meeting Abstract
Oncology
Keiichi Nakayama