Article
Biochemistry & Molecular Biology
Zhuoma Yinsheng, Ko Miyoshi, Yuanyuan Qin, Yuuki Fujiwara, Takeshi Yoshimura, Taiichi Katayama
Summary: This study found that TMEM67 plays a key role in both ciliogenesis and cilium length regulation, and its gating function in the transition zone is independent of RPGRIP1L/CEP290/NPHP5 recruitment. The results suggest that aberrant cilium elongation may contribute to the pathogenesis of TMEM67-linked ciliopathies.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Genetics & Heredity
Ke Ning, Emilie Song, Brent E. Sendayen, Philipp P. Prosseda, Kun-Che Chang, Alireza Ghaffarieh, Jorge A. Alvarado, Biao Wang, Kathryn M. Haider, Nicolas F. Berbari, Yang Hu, Yang Sun
Summary: Senior-Loken syndrome is a rare genetic disorder caused by mutations in the NPHP1 gene, leading to renal and retinal degeneration. The absence of NPHP1 affects the subcellular distribution of ciliary proteins, potentially altering the composition of phosphoinositides in the ciliary membrane.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Article
Genetics & Heredity
Ke Ning, Emilie Song, Brent E. Sendayen, Philipp P. Prosseda, Kun-Che Chang, Alireza Ghaffarieh, Jorge A. Alvarado, Biao Wang, Kathryn M. Haider, Nicolas F. Berbari, Yang Hu, Yang Sun
Summary: Senior-Loken syndrome is a rare genetic disorder that results in nephronophthisis and retinal degeneration. A mutation in the NPHP1 gene is the most common cause of juvenile nephronophthisis. In this case study, a 9-year-old boy with Senior-Loken syndrome required bilateral nephrectomy and renal transplant due to deteriorating renal function. Immunohistochemistry and electron microscopy showed disorganized cystic structures with loss of cilia in renal tubules, suggesting a role of NPHP1 in regulating ciliary phosphoinositide composition in the ciliary membrane of renal tubular cells.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Editorial Material
Cell Biology
Asma Boukhalfa, Federica Roccio, Nicolas Dupont, Patrice Codogno, Etienne Morel
Summary: The primary cilium serves as a sensor for extracellular stress stimuli, with the autophagy protein ATG16L1 playing a crucial role in PC dynamics. Interaction between IFT20 and ATG16L1 affects phospholipid accumulation in ciliary structures, while INPP5E is involved in proper PC function. Disruption of the ATG16L1-IFT20 complex alters INPP5E trafficking, revealing a novel autophagy-independent function of ATG16L1 in regulating PC dynamics.
Article
Biology
Simon Stilling, Theodoros Kalliakoudas, Hannah Benninghoven-Frey, Takanari Inoue, Bjorn H. Falkenburger
Summary: The level of PIP2 in the ciliary membrane determines the length of primary cilia. Various pathways converge on PIP2 to induce ciliary fission, which is dependent on actin, AurkA and HDAC6. This study reveals the importance of PIP2 in the stability and turnover of ciliary membrane.
COMMUNICATIONS BIOLOGY
(2022)
Article
Cell Biology
Ping Shi, Jia Tian, Julianne C. Mallinger, Dahao Ling, Loic P. Deleyrolle, Jeremy C. Mcintyre, Tamara Caspary, Joshua J. Breunig, Matthew R. Sarkisian
Summary: This study found that increasing ARL13B expression in glioma cells can promote the accumulation of SMO and GLI2 in cilia, and this accumulation is resistant to SMO inhibitors. Furthermore, the increase in ARL13B also leads to changes in ciliary membrane characteristics and retrograde transport, which further promote SMO and GLI accumulation in glioma cells.
Article
Biochemistry & Molecular Biology
Jhan-Jhang Syu, Chieh-Hsiang Chang, Pei-Yu Chang, Chia-Hsiung Liu, Chia-Jung Yu, Tzuu-Shuh Jou
Summary: The study shows that galectin 8 promotes the rapid elongation of primary cilia by binding to lipid raft components at the base of cilia and interfering with the interaction between caveolin 1 and TMEM231. The functional barrier of the transition zone is disrupted, resulting in the redistribution of cilia proteins and the elongation of primary cilia.
Article
Biology
Hantian Qiu, Sayaka Fujisawa, Shohei Nozaki, Yohei Katoh, Kazuhisa Nakayama
Summary: The binding of INPP5E to ARL13B is crucial for its steady-state localization on the ciliary membrane, but is not necessary for its entry into cilia.
Article
Biochemistry & Molecular Biology
Taishi Kanamaru, Annett Neuner, Bahtiyar Kurtulmus, Gislene Pereiral
Summary: Understanding the segmentation of primary cilia is important for controlling their length and signaling functions. Perturbations leading to cilia over-elongation have been shown to impact different segments of the cilia axonemes, influencing cilia behavior. Septins have been identified as novel repressors of distal segment (DS) growth.
Article
Biology
Dario Cilleros-Rodriguez, Raquel Martin-Morales, Pablo Barbeito, Abhijit Deb Roy, Abdelhalim Loukil, Belen Sierra-Rodero, Gonzalo Herranz, Olatz Pampliega, Modesto Redrejo-Rodriguez, Sarah C. Goetz, Manuel Izquierdo, Takanari Inoue, Francesc R. Garcia-Gonzalo
Summary: Primary cilia are membrane protrusions responsible for sensory functions, and dysfunction of these cilia can lead to ciliopathies. INPP5E, a phosphoinositide phosphatase, is mutated in ciliopathies such as Joubert syndrome. This study uncovers the mechanism of INPP5E ciliary targeting and interactions, providing valuable insights into ciliary functions and related disorders.
Review
Biochemistry & Molecular Biology
Renshuai Zhang, Jianming Tang, Tianliang Li, Jun Zhou, Wei Pan
Summary: Primary cilia are mechanosensory organelles that regulate cellular physiological processes. INPP5E is an enzyme that plays a key role in phosphoinositide metabolism and works synergistically with ciliary membrane-related proteins to maintain cilia homeostasis and function.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biology
Sayaka Fujisawa, Hantian Qiu, Shohei Nozaki, Shuhei Chiba, Yohei Katoh, Kazuhisa Nakayama
Summary: INPP5E is localized on the ciliary membrane via its prenyl moiety, with the ARL3 and ARL13B GTPases contributing to maintaining this localization through different mechanisms, with ARL13B mainly determining the ciliary localization of INPP5E through direct binding to it.
Article
Chemistry, Physical
Grace A. DeSalvo, Grayson R. Hoy, Isabelle M. Kogan, John Z. Li, Elise T. Palmer, Emilio Luz-Ricca, Paul Scemama de Gialluly, Kristin L. Wustholz
Summary: This study introduces a blinking-based multiplexing approach to differentiate spectrally overlapped emitters. By analyzing the blinking dynamics of fluorescent probes on glass, a blinking metric with 93.5% classification accuracy is obtained. Furthermore, using a deep learning algorithm for classification, up to 96.6% accuracy is achieved.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2022)
Article
Cell Biology
Kirill Ukhanov, Cedric Uytingco, Warren Green, Lian Zhang, Stephane Schurmans, Jeffrey R. Martens
Summary: The lipid composition of the cilia membrane plays a critical role in cilia formation, maintenance and function. Deletion of a specific gene leads to remodeling of ciliary phospholipids and elongation of cilia, impacting odor adaptation and response kinetics. Gene replacement restores ciliary localization and odor response kinetics.
JOURNAL OF CELL SCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Kwangjin Park, Michel R. Leroux
Summary: The transition zone (TZ) of the cilium acts as a diffusion barrier, ensuring ciliary autonomy and homeostasis by its unique complement and spatial organization of proteins, a protein picket fence, a specialized lipid microdomain, differential membrane curvature and thickness, and a size-selective molecular sieve. Understanding the TZ is important not only for illuminating essential aspects of human cell signaling, physiology, and development, but also for unraveling how TZ dysfunction contributes to ciliopathies affecting multiple organ systems.
Article
Biochemistry & Molecular Biology
Sarah E. Conduit, Elizabeth M. Davies, Lisa M. Ooms, Rajendra Gurung, Meagan J. McGrath, Sandra Hakim, Denny L. Cottle, Ian M. Smyth, Jennifer M. Dyson, Christina A. Mitchell
HUMAN MOLECULAR GENETICS
(2020)
Article
Biochemistry & Molecular Biology
David A. Sheffield, Lene R. Jepsen, Sandra J. Feeney, Micka C. Bertucci, Absorn Sriratana, Monica J. Naughtin, Jennifer M. Dyson, Ross L. Coppel, Christina A. Mitchell
JOURNAL OF BIOLOGICAL CHEMISTRY
(2019)
Article
Cell Biology
Jessica L. Teo, Guillermo A. Gomez, Saroja Weeratunga, Elizabeth M. Davies, Ivar Noordstra, Srikanth Budnar, Hiroko Katsuno-Kambe, Meagan J. McGrath, Suzie Verma, Vanesa Tomatis, Bipul R. Acharya, Lakshmi Balasubramaniam, Rachel M. Templin, Kerrie-Ann Mcmahon, Yoke Seng Lee, Robert J. Ju, Samantha J. Stebhens, Benoit Ladoux, Christina A. Mitchell, Brett M. Collins, Robert G. Parton, Alpha S. Yap
DEVELOPMENTAL CELL
(2020)
Article
Biochemistry & Molecular Biology
Hon Yan K. Yip, Annabel Chee, Ching-Seng Ang, Sung-Young Shin, Lisa M. Ooms, Zainab Mohammadi, Wayne A. Phillips, Roger J. Daly, Timothy J. Cole, Roderick T. Bronson, Lan K. Nguyen, Tony Tiganis, Robin M. Hobbs, Catriona A. McLean, Christina A. Mitchell, Antonella Papa
Article
Multidisciplinary Sciences
Nuthasuda Srijakotre, Heng-jia Liu, Max Nobis, Joey Man, Hon Yan Kelvin Yip, Antonella Papa, Helen E. Abud, Kurt I. Anderson, Heidi C. E. Welch, Tony Tiganis, Paul Timpson, Catriona A. McLean, Lisa M. Ooms, Christina A. Mitchell
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Editorial Material
Cell Biology
Matthew J. Eramo, Rajendra Gurung, Christina A. Mitchell, Meagan J. McGrath
Summary: Autophagic lysosome reformation (ALR) is crucial for recycling autophagy membranes to form lysosomes. INPP5K, an enzyme that converts PtdIns(4,5)P-2 to PtdIns4P, plays a key role in this process in skeletal muscle. Mutations in INPP5K can lead to muscular dystrophy by disrupting ALR and lysosome homeostasis in muscles.
Article
Biochemistry & Molecular Biology
Laura D'Andrea, Christina M. Lucato, Elsa A. Marquez, Yong-Gang Chang, Srgjan Civciristov, Chantel Mastos, Christopher J. Lupton, Cheng Huang, Hans Elmlund, Ralf B. Schittenhelm, Christina A. Mitchell, James C. Whisstock, Michelle L. Halls, Andrew M. Ellisdon
Summary: The PTEN:P-Rex2 complex assembly inhibits the activity of both proteins and dysregulation can drive PI3K-AKT signaling and cellular proliferation. The study revealed the interactions between PTEN and P-Rex2, proposing a class of gain-of-function mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.
Article
Multidisciplinary Sciences
Samuel J. Rodgers, Lisa M. Ooms, Viola M. J. Oorschot, Ralf B. Schittenhelm, Elizabeth Nguyen, Sabryn A. Hamila, Natalie Rynkiewicz, Rajendra Gurung, Matthew J. Eramo, Absorn Sriratana, Clare G. Fedele, Franco Caramia, Sherene Loi, Genevieve Kerr, Helen E. Abud, Georg Ramm, Antonella Papa, Andrew M. Ellisdon, Roger J. Daly, Catriona A. McLean, Christina A. Mitchell
Summary: INPP4B functions as a tumor suppressor in triple negative breast cancer by converting PI(3,4)P-2 to PI(3)P. However, in PIK3CA-mutant ER+ breast cancers, INPP4B enhances cell proliferation and tumor growth by promoting PI3K alpha-dependent late endosome formation and trafficking that activates Wnt/beta -catenin signaling.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Alessia Floerchinger, Kendelle J. Murphy, Sharissa L. Latham, Sean C. Warren, Andrew T. McCulloch, Young-Kyung Lee, Janett Stoehr, Pauline Melenec, Cris S. Guaman, Xanthe L. Metcalf, Victoria Lee, Anaiis Zaratzian, Andrew Da Silva, Michael Tayao, Sonia Rolo, Monica Phimmachanh, Ghazal Sultani, Laura McDonald, Susan M. Mason, Nicola Ferrari, Lisa M. Ooms, Anna-Karin E. Johnsson, Heather J. Spence, Michael F. Olson, Laura M. Machesky, Owen J. Sansom, Jennifer P. Morton, Christina A. Mitchell, Michael S. Samuel, David R. Croucher, Heidi C. E. Welch, Karen Blyth, C. Elizabeth Caldon, David Herrmann, Kurt Anderson, Paul Timpson, Max Nobis
Summary: Assessing drug response within live native tissue provides increased fidelity in optimizing efficacy and minimizing off-target effects. Using single-cell intravital imaging, this study demonstrates that Rac1 inhibition can reduce tumor progression and metastases to improve overall survival in an autochthonous setting. The study also reveals enhanced Rac1 activity of cells near live tumor vasculature, and how Rac1 inhibition can enhance tumor cell vulnerability to fluid-flow-induced shear stress for better anti-metastatic response during transit to secondary sites.
Article
Multidisciplinary Sciences
Chrysovalantou E. Xirouchaki, Yaoyao Jia, Meagan J. McGrath, Spencer Greatorex, Melanie Tran, Troy L. Merry, Dawn Hong, Matthew J. Eramo, Sophie C. Broome, Jonathan S. T. Woodhead, Randall F. D'souza, Jenny Gallagher, Ekaterina Salimova, Cheng Huang, Ralf B. Schittenhelm, Junichi Sadoshima, Matthew J. Watt, Christina A. Mitchell, Tony Tiganis
Summary: ROS generated by NOX4 in skeletal muscle play a crucial role in promoting muscle function, maintaining redox balance, and preventing the development of insulin resistance. Reductions in NOX4 levels in skeletal muscle contribute to insulin resistance development, affecting exercise capacity and antioxidant defense mechanisms.
Article
Biochemistry & Molecular Biology
Samuel J. Rodgers, Emily Jones, Senthil Arumugam, Sabryn A. Hamila, Jill Danne, Rajendra Gurung, Matthew J. Eramo, Randini Nanayakkara, Georg Ramm, Meagan J. McGrath, Christina A. Mitchell
Summary: This study reveals an endosome-dependent phosphoinositide pathway that regulates lysosome repopulation during basal autophagy. This pathway involves the sequential actions of PI3K alpha, INPP4B, and PIKfyve, which contribute to autophagic degradation and protection against proteotoxic stress. These findings provide insights into the coordination of lysosome regeneration during autophagy.
Editorial Material
Cell Biology
Samuel J. Rodgers, Emily Jones, Christina A. Mitchell, Meagan J. McGrath
Summary: Macroautophagy/autophagy plays a crucial role in maintaining protein and organelle quality and protecting against aging and neurodegeneration. In nutrient-rich conditions, a sequential phosphoinositide conversion pathway enables lysosome repopulation to support basal autophagy.
Review
Cell Biology
Randini Nanayakkara, Rajendra Gurung, Samuel J. J. Rodgers, Matthew J. J. Eramo, Georg Ramm, Christina A. A. Mitchell, Meagan J. J. McGrath
Summary: This review provides an overview of the importance of lysosome reformation in maintaining autophagy function and the role of ALR dysfunction in various diseases.
Article
Oncology
Samuel J. Rodgers, Lisa M. Ooms, Christina A. Mitchell
Summary: Wnt/β-catenin signaling is hyperactivated in many human cancers, including 50% of breast cancers. Repurposing the FDA-approved drug pyrvinium, which suppresses Wnt signaling, may be a more efficient method to target this pathway. We demonstrate that breast cancer cells with high expression of the oncogene INPP4B are selectively sensitive to pyrvinium treatment, suggesting its potential as a therapeutic strategy for breast cancers with high INPP4B expression.