Review
Pharmacology & Pharmacy
Baoqi Yu, Xia Wang, Yanting Song, Guomin Xie, Shiyu Jiao, Li Shi, Xuejie Cao, Xinyao Han, Aijuan Qu
Summary: Cardiovascular diseases are the leading cause of death worldwide, and hypoxia-inducible factors (HIFs) play an important role in their pathogenesis. Recent studies have revealed the role of cell-specific HIFs in various cardiovascular diseases, but the potential clinical application of HIF inhibitors in the treatment of cardiovascular diseases is not well understood.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Cell Biology
Balaji T. Moorthy, Chunhua Jiang, Devang M. Patel, Yuguang Ban, Corin R. O'Shea, Akhilesh Kumar, Tan Yuan, Michael D. Birnbaum, Aldrin Gomes, Xi Chen, Flavia Fontanesi, Theodore J. Lampidis, Antoni Barrientos, Fangliang Zhang
Summary: This study identifies an alternative oxygen-sensing pathway regulated by ATE1, which controls the hypoxic response and glycolysis in mammalian cells by arginylating HIF1α. This pathway plays an important regulatory role in human tumors.
DEVELOPMENTAL CELL
(2022)
Article
Cell Biology
Bo Zhang, Yan Chen, Lei Bao, Weibo Luo
Summary: This study demonstrates that hypoxia upregulates the expression of GPT2 in GBM cells through HIF-2 activation. GPT2 is localized in the nucleus and mitochondria and can decrease α-ketoglutarate levels in GBM cells. Inhibition of GPT2 can reduce GBM cell growth and migration, and knockout of GPT2 inhibits GBM tumor growth in mice.
Review
Cell Biology
Elena V. Mitroshina, Maria O. Savyuk, Evgeni Ponimaskin, Maria V. Vedunova
Summary: Hypoxia is a common pathological condition induced by various events, with the body's adaptation to it being crucial for health and disease. HIFs, a family of transcription factors, play a key role in cellular responses to hypoxia and are increasingly viewed as potential targets for treating a range of hypoxia-associated diseases. The role of HIFs in adaptation to hypoxia is universal across tissue types, including the CNS, where they are involved in regulating neurogenesis, nerve cell differentiation, and neuronal apoptosis, potentially offering new therapeutic opportunities.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biology
Corine M. van der Weele, William R. Jeffery
Summary: Dark caves lacking primary productivity expose subterranean animals to hypoxia. Cavefish cope with hypoxia by increasing erythrocyte development and constitutive hif1 gene overexpression.
Article
Urology & Nephrology
Szu-Yu Pan, Pei-Zhen Tsai, Yu-Hsiang Chou, Yu-Ting Chang, Fan-Chi Chang, Yen-Ling Chiu, Wen-Chih Chiang, Tien Hsu, Yung-Ming Chen, Tzong-Shinn Chu, Shuei-Liong Lin
Summary: PHD inhibitors are effective in treating CKD-associated anemia by stabilizing HIF and increasing erythropoiesis. However, their impact on kidney fibrosis is inconsistent due to the context-dependent effects of HIF. Studies on pericytes suggest that HIF stabilization in these cells may not negatively affect kidney fibrosis despite increased erythropoietin production.
KIDNEY INTERNATIONAL
(2021)
Review
Pharmacology & Pharmacy
Zirong Pan, Guodong Ma, Linglei Kong, Guanhua Du
Summary: Stroke is an acute cerebrovascular disease caused by sudden rupture or blockage of blood vessels in the brain, and HIF-1 plays an important role in regulating various pathways in the pathological process. The roles of HIF-1 in stroke are controversial, involving factors such as ischemic time and degree, and its regulatory mechanisms include inflammation, autophagy, oxidative stress, and apoptosis.
PHARMACOLOGICAL RESEARCH
(2021)
Review
Immunology
Jinwei Zhang, Xiaoqian Wu, Jideng Ma, Keren Long, Jing Sun, Mingzhou Li, Liangpeng Ge
Summary: Hypoxia and HIF signaling have important regulatory roles in cell biology, but their role in B cell biology is still controversial. Studies have found that hypoxia niches exist in different developmental stages of B cells, suggesting that hypoxia and HIF signaling may play a crucial role in the development, metabolism, and function of B cells. A better understanding of the role of hypoxia in B cell-mediated adaptive immunity could provide new strategies for vaccine adjuvant research and the treatment of immunity-related or infectious diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Medicine, Research & Experimental
Min Kyung Park, Jun Ji, Keeok Haam, Tae-Hee Han, Seona Lim, Mi-Jung Kang, Soon Sung Lim, Hyun Seung Ban
Summary: Licochalcone A, a component of Glycyrrhiza uralensis, demonstrates potential as a therapeutic agent in hypoxic cancer cells by inhibiting HIF-1 alpha accumulation and mitochondrial respiration, leading to increased oxygen content and suppression of cancer cell viability.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Bo Zhang, Yan Chen, Xiaolei Shi, Mi Zhou, Lei Bao, Kimmo J. Hatanpaa, Toral Patel, Ralph J. DeBerardinis, Yingfei Wang, Weibo Luo
Summary: This study reveals that hypoxia induces upregulation of the BCAA transporter LAT1 and the BCAA metabolic enzyme BCAT1 in human glioblastoma cells through the mediation of HIF-1 and HIF-2. HIF-1α plays a critical role in hypoxia-induced BCAT1 expression, and knockout of HIFs reduces glutamate labeling from BCAAs in GBM cells. Inhibition of BCAT1 inhibits GBM cell growth under hypoxia, highlighting a previously unrecognized HIF-dependent metabolic pathway.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Review
Engineering, Biomedical
Kelsey G. DeFrates, Daniela Franco, Ellen Heber-Katz, Phillip B. Messersmith
Summary: Traditional approaches in regenerative medicine face limitations in translation and commercialization, prompting the development of therapies that stimulate endogenous processes for regeneration. Recent studies highlight the potential of oxygen-sensing pathways, with upregulation of HIF-1α showing promise in modulating cell metabolism and plasticity for tissue regeneration.
Article
Biochemistry & Molecular Biology
Giorgia F. Camagni, Giovanni Minervini, Silvio C. E. Tosatto
Summary: The Prolyl Hydroxylases (PHDs) are a family of enzymes that regulate cell oxygen-sensing by hydroxylating hypoxia-inducible transcription factors alpha (HIFs-alpha) and promoting their degradation. Hypoxia inhibits PHDs activity, leading to HIFs-alpha stabilization and cell adaptation to low oxygen levels. The different isoforms of PHDs have varying effects on tumor progression. Molecular dynamics simulations, conservation analysis, and binding free energy calculations were used to study the binding properties and substrate affinity of PHD2 with HIF-1 alpha and HIF-2 alpha. The findings suggest that the PHD2 C-terminus may play a role in regulating PHD activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Endocrinology & Metabolism
Dan Du, Yugang Zhang, Canjun Zhu, Hong Chen, Jia Sun
Summary: The earliest function of hypoxia-inducible factor (HIF) was to respond to hypoxic conditions as a transcription factor. Recent studies have shown that HIF plays an essential role in central regulation of metabolism, affecting the central nervous system's response to glucose, inflammation, and hormonal influence on systemic metabolism. HIF primarily inhibits energy uptake and promotes energy expenditure in the hypothalamus, with its role depending on various factors and mechanisms within the hypothalamus.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Review
Pharmacology & Pharmacy
Chunying Xiao, Sheng Liu, Ge Ge, Hao Jiang, Liezhi Wang, Qi Chen, Chong Jin, Jinggang Mo, Jin Li, Kunpeng Wang, Qianqian Zhang, Jianyu Zhou
Summary: Hepatocellular carcinoma (HCC) is a common digestive malignancy and a leading cause of cancer mortality worldwide. Local ablation therapies, such as radiofrequency ablation (RFA) and high-intensity focused ultrasound (HIFU) ablation, have shown effectiveness in treating HCC. However, the molecular mechanisms and HCC recurrence after ablation still need further understanding.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Medicine, Research & Experimental
Tripti Singh, Pallabi Banerjee, Uditi, Sarita Kumari, Anita Chopra, Nagendra Singh, Imteyaz Qamar
Summary: Regucalcin regulates intracellular Ca2+ homeostasis and intracellular signaling pathways. Its expression in hypoxia is upregulated by HIF-1α through direct binding to the HRE binding motifs within the Regucalcin promoter.
Review
Biochemistry & Molecular Biology
Kazuhiro Iwai
Summary: Linear ubiquitination is a crucial post-translational modification that regulates protein function, with key roles in immune signaling and cell death regulation. Dysregulation of linear ubiquitination is associated with various human diseases, including autoinflammation and cancer.
Article
Biochemistry & Molecular Biology
Daichi Morimoto, Erik Walinda, Shingo Takashima, Mayu Nishizawa, Kazuhiro Iwai, Masahiro Shirakawa, Kenji Sugase
Summary: Structural dynamic heterogeneity was observed in the two ubiquitin moieties of K48-linked diubiquitin through NMR spectroscopic analyses. These heterogeneous structural fluctuations, linked to an increase in susceptibility to phosphorylation by PINK1, may distinguish individual ubiquitin moieties in a chain, aiding efficiency and specificity in post-translational modifications.
Article
Multidisciplinary Sciences
Kazuhiro Iwai
Summary: Linear ubiquitination, which is specific to animals, involves the formation of a unique type of ubiquitin chain linked through the N-terminal Met of ubiquitin. It plays a critical role in immune signaling and cell death regulation. Dysregulation of linear ubiquitination mediated by LUBAC underlies various human diseases.
PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES
(2021)
Article
Multidisciplinary Sciences
Yukiko Yoshida, Makoto Asahina, Arisa Murakami, Junko Kawawaki, Meari Yoshida, Reiko Fujinawa, Kazuhiro Iwai, Ryuichi Tozawa, Noriyuki Matsuda, Keiji Tanaka, Tadashi Suzuki
Summary: Mutation in the NGLY1 gene leads to a recessive disorder in humans. Findings in this study suggest that dysfunction of the proteasome caused by accumulation of N-glycoproteins, particularly NRF1 ubiquitinated by SCFFBS2, contributes to the pathogenesis resulting from NGLY1 deficiency.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Meeting Abstract
Hematology
Koji Jimbo, Shuhei Koide, Takahiro Ito, Arinobu Tojo, Katsuhiro Sasaki, Kazuhiro Iwai, Atsushi Iwama, Yasuhito Nannya, Takaaki Konuma
Article
Clinical Neurology
Silvia Nitschke, Mitchell A. Sullivan, Sharmistha Mitra, Charlotte R. Marchioni, Jennifer P. Y. Lee, Brandon H. Smith, Saija Ahonen, Jun Wu, Erin E. Chown, Peixiang Wang, Sara Petkovic, Xiaochu Zhao, Laura F. DiGiovanni, Ami M. Perri, Lori Israelian, Tamar R. Grossman, Holly Kordasiewicz, Francisco Vilaplana, Kazuhiro Iwai, Felix Nitschke, Berge A. Minassian
Summary: This study investigates the influence of glucan chain length on precipitation and the disease caused by abnormal glycogen structure. The authors found that the glycogen pathology of RBCK1 deficiency is similar to malin-deficient Lafora disease and can be rescued by downregulating glycogen synthase.
Article
Biochemical Research Methods
Erik Walinda, Daichi Morimoto, Tomoki Sorada, Kazuhiro Iwai, Kenji Sugase
Summary: A simple strategy was developed to successfully produce the isolated LUBAC LTM domain in high yield and high purity in bacteria, which will benefit LTM-based drug-screening efforts and similar cases requiring isolation of smaller folded fragments from larger protein complexes. The strategy involves tandem expression, efficient monitoring of expression and solubility, and gentle low-temperature folding. Stably folded LTM was confirmed by size-exclusion chromatography and NMR spectroscopy, providing sufficient high-purity protein for structural studies from small-scale cultures.
PROTEIN EXPRESSION AND PURIFICATION
(2021)
Review
Cell Biology
Yasuhiro Fuseya, Kazuhiro Iwai
Summary: Linear ubiquitin chains play crucial roles in cell survival, proliferation, immune response, and bacterial clearance; these chains regulate physiological processes by controlling inflammatory responses and cell death; LUBAC, a complex containing two different ubiquitin ligases, interacts with deubiquitinating enzymes to regulate linear ubiquitination.
Article
Biochemistry & Molecular Biology
Sota Kuno, Hiroaki Fujita, Yu-Ki Tanaka, Yasumitsu Ogra, Kazuhiro Iwai
Summary: NCOA4 acts as a crucial autophagy adaptor protein that regulates ferritin fate under both iron repletion and depletion conditions, maintaining cellular iron homeostasis. By forming insoluble condensates, NCOA4 prevents excessive iron storage in cells and facilitates ferritin delivery to lysosomes, effectively balancing iron levels in the cell.
Article
Biochemistry & Molecular Biology
Yutaka Shinkawa, Koshi Imami, Yasuhiro Fuseya, Katsuhiro Sasaki, Koichiro Ohmura, Yasushi Ishihama, Akio Morinobu, Kazuhiro Iwai
Summary: This study reveals the important roles of linear ubiquitin chains and ABIN1 in immune signaling, particularly in regulating cell death and NF-kappa B signaling. The researchers also discovered that phosphorylated ABIN1 functions as a selective autophagy receptor in TLR signaling, leading to the degradation of signaling proteins and attenuation of NF-kappa B signaling.
Article
Immunology
Matthew J. Wood, Jeffrey N. Marshall, Victoria L. Hartley, Ta-Chiang Liu, Kazuhiro Iwai, Thaddeus S. Stappenbeck, Donna A. MacDuff
Summary: Patients with mutations in HOIL1 may experience immune disorders including intestinal inflammation. This study found that HOIL1 plays a key role in regulating type 2 inflammation in the small intestine, affecting cell proliferation and gene expression. Commensal microbes may also contribute to intestinal inflammation.
MUCOSAL IMMUNOLOGY
(2022)
Article
Oncology
Yusuke Sakamoto, Katsuhiro Sasaki, Mayuki Omatsu, Kensuke Hamada, Yuki Nakanishi, Yoshiro Itatani, Kenji Kawada, Kazutaka Obama, Hiroshi Seno, Kazuhiro Iwai
Summary: Disruption of the intestinal epithelial barrier and dysregulation of macrophages contribute to the pathogenesis of inflammatory bowel diseases (IBDs). In this study, the role of linear ubiquitination in intestinal epithelial cells (IECs) and macrophages during intestinal inflammation was investigated using mouse models of IBD. The results showed that loss of linear ubiquitination activity in IECs induced mucosal inflammation and augmented IEC death, while defective LUBAC ligase activity in macrophages ameliorated DSS-induced colitis by reducing macrophage infiltration and expression of inflammatory cytokines.
JOURNAL OF PATHOLOGY
(2023)
Article
Oncology
Koji Jimbo, Ayuna Hattori, Shuhei Koide, Takahiro Ito, Katsuhiro Sasaki, Kazuhiro Iwai, Yasuhito Nannya, Atsushi Iwama, Arinobu Tojo, Takaaki Konuma
Summary: We investigated the role of Hoip, a catalytic subunit of LUBAC, in adult hematopoiesis and myeloid leukemia. Conditional deletion of Hoip or inhibition with small-molecule inhibitors led to longer survival and reduced leukemia burden. Structural and functional analysis revealed the importance of LUBAC ligase activity and subunit interaction in leukemia propagation. Hoip regulated the oxidative phosphorylation pathway in leukemia, but not in normal hematopoietic cells. Inhibition of Hoip improved survival and suppressed propagation in murine and patient-derived xenograft models of myeloid leukemia. In conclusion, inhibition of LUBAC activity may be a valid therapeutic target for myeloid leukemia.
Article
Biochemistry & Molecular Biology
Katsuhiro Sasaki, Yoshie Hayamizu, Ryuji Murakami, Masakazu Toi, Kazuhiro Iwai
Summary: Tumor-elicited inflammation confers tumorigenic properties, including cell death resistance, proliferation, or immune evasion. We investigated linear ubiquitination in tumors, which enhances NF-κB signaling pathway and prevents extrinsic programmed cell death, especially in tumor cells around a necrotic core. Linear ubiquitination allows melanomas to tolerate the hostile tumor microenvironment and maintain a necrosis-containing morphology, promoting immune-mediated tumor eradication.
Article
Biochemistry & Molecular Biology
Sota Kuno, Kazuhiro Iwai
Summary: To maintain cellular iron homeostasis and avoid its toxicity, cells possess iron-sensing proteins like nuclear receptor coactivator 4 (NCOA4) which regulates ferritin fate. We have discovered an additional iron-sensing mechanism of NCOA4 involving an iron-sulfur cluster that enables recognition by the HERC2 ubiquitin ligase, leading to degradation and inhibition of ferritinophagy in iron-replete conditions. Both condensation and ubiquitin-mediated degradation of NCOA4 can coexist in the same cell, with the selection of pathways determined by cellular oxygen tension.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)