Review
Biology
Xiaoyu Tian, Huijie Zhao, Jun Zhou
Summary: The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and lead to ciliopathies, notably Bardet-Biedl syndrome. An improved understanding of BBSome-mediated biological events and molecular mechanisms is expected to help advance the development of diagnostic and therapeutic approaches for BBSome-related diseases.
Article
Multidisciplinary Sciences
Rui-Kai Zhang, Wei-Yue Sun, Yan-Xia Liu, Emma Y. Zhang, Zhen-Chuan Fan
Summary: This study reveals the mechanism of signal protein export from cilia via the RABL2-ARL3 cascade-mediated outward BBSome transition zone diffusion pathway.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yan-Xia Liu, Wen -Juan Li, Rui-Kai Zhang, Sheng-Nan Sun, Zhen-Chuan Fan
Summary: Certain ciliary signaling proteins are transported from the tip to the base of cilia via retrograde intraflagellar transport (IFT), facilitated by the BBSome and ARL13. The interaction between ARL13GTP and BBS3GTP at the ciliary tip plays a crucial role in properly coupling the BBSome with signaling cargo. This understanding provides mechanistic insights into the defects seen in hedgehog signaling in humans with ARL13b and BBS3 mutations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Wei-Yue Sun, Bin Xue, Yan-Xia Liu, Rui-Kai Zhang, Rong-Chao Li, Wen Xin, Mingfu Wu, Zhen-Chuan Fan
Summary: LZTFL1 maintains BBSome dynamics in cilia by controlling BBSome recruitment to the basal body and its reassembly at the ciliary tip, thus regulating ciliary signaling.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Michael W. Stuck, Weng Man Chong, Jung-Chi Liao, Gregory J. Pazour
Summary: Primary cilia are essential for development and health, and dysfunction is associated with a range of human pathologies. The small GTPase Rab34 was identified as a key protein in ciliary formation, particularly important for internal assembly pathway. Additionally, it was found that IMCD3 cells can utilize the internal assembly pathway for ciliogenesis.
Article
Multidisciplinary Sciences
Markus Masek, Christelle Etard, Claudia Hofmann, Andreas J. Huelsmeier, Jingjing Zang, Masanari Takamiya, Matthias Gesemann, Stephan C. F. Neuhauss, Thorsten Hornemann, Uwe Straehle, Ruxandra Bachmann-Gagescu
Summary: The study identifies the role of Bbs1 in lipid homeostasis of photoreceptor outer segments, which may contribute to vision loss in patients with Bardet-Biedl syndrome.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Yan-Xia Liu, Rui-Kai Zhang, Zhen-Chuan Fan
Summary: BBSome is a key component for the export of signaling proteins in cilia. IFT27 binds its partner IFT25 to form the IFT25/27 complex, which is necessary for BBSome reassembly. The interaction between IFT25/27 and the IFT-B subcomplex core IFT-B1 is enhanced by GTP-loading onto IFT27. The presence of IFT25/27 at the ciliary tip facilitates BBSome-dependent PLD export, regardless of the nucleotide state of IFT27.
JOURNAL OF CELLULAR PHYSIOLOGY
(2023)
Article
Cell Biology
Toneisha Stubbs, James I. Bingman, Jason Besse, Kirk Mykytyn
Summary: Primary cilia are important for neuronal functions and their dysfunction is linked to ciliopathies. Bardet-Biedl syndrome proteins play a crucial role in trafficking G protein-coupled receptors (GPCRs) in neuronal cilia, and their absence leads to abnormal localization of signaling proteins in the brain.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Xiumin Yan, Yidong Shen
Summary: Primary cilia are important sensory organelles in cells, with intraflagellar transport essential for their assembly, maintenance, and function. Recent studies have highlighted the critical regulatory roles of three ciliary Rab-like small GTPases in ciliary BBSome transport.
Review
Physiology
Himanshu Malhotra, Cassandra L. Barnes, Peter D. Calvert
Summary: Retinal photoreceptors are neurons that convert light into electrical signals for transmission to the brain. The functions of photoreceptors are divided into three specialized compartments- the outer segment, inner segment, and pre-synaptic terminal. Disruption of this compartmentalization can lead to devastating blinding diseases.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2021)
Article
Cell Biology
Dong Yun Kim, Yu Jin Sub, Hye-Youn Kim, Kyeong Jee Cho, Won Il Choi, Yo Jun Choi, Min Goo Lee, Friedhelm Hildebrandt, Heon Yung Gee
Summary: LRRC6 functions as an assembly factor for dynein arms in motile ciliated cells. We investigated its role in the active nuclear translocation of FOXJ1, a master regulator for cilia-associated gene transcription. Knockout of LRRC6 hindered the assembly of cilia components and resulted in decreased expression of cilia-related proteins and transcripts.
CELL COMMUNICATION AND SIGNALING
(2023)
Article
Endocrinology & Metabolism
Deng-Fu Guo, Ronald A. Merrill, Lan Qian, Ying Hsu, Qihong Zhang, Zhihong Lin, Daniel R. Thedens, Yuriy M. Usachev, Isabella Grumbach, Val C. Sheffield, Stefan Strack, Kamal Rahmouni
Summary: The study reveals that the BBSome protein complex plays a critical role in regulating mitochondrial dynamics and function. The disruption of the BBSome leads to excessive fusion of mitochondria in various cell types, and this morphological change is associated with functional abnormalities, including reduced oxygen consumption rate and altered mitochondrial distribution and calcium handling. Mechanistically, the BBSome modulates the activity of the key regulator protein DRP1 through regulating its phosphorylation and translocation, and rescuing the decrease in DRP1 activity can normalize the defects induced by BBSome deficiency.
MOLECULAR METABOLISM
(2023)
Article
Biochemistry & Molecular Biology
Francesco Chiuso, Rossella delle Donne, Giuliana Giamundo, Laura Rinaldi, Domenica Borzacchiello, Federica Moraca, Daniela Intartaglia, Rosa Iannucci, Emanuela Senatore, Luca Lignitto, Corrado Garbi, Paolo Conflitti, Bruno Catalanotti, Ivan Conte, Antonio Feliciello
Summary: Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, renal abnormalities, postaxial polydactyly, and developmental defects. The E3 ubiquitin ligase PJA2 has been identified as a regulator of the BBSome, an octameric complex that controls ciliary trafficking. Ubiquitylation of BBS1 by PJA2 stabilizes the BBSome and promotes its binding to BBS3, leading to proper ciliary membrane targeting. Disruption of PJA2 or expression of a ubiquitylation-defective BBS1 mutant affects GPCR trafficking and gene transcription, recapitulating the BBS phenotype in a medaka fish model.
Article
Multidisciplinary Sciences
Ricardo Fradique, Erika Causa, Clara Delahousse, Jurij Kotar, Laetitia Pinte, Ludovic Vallier, Marta Vila-Gonzalez, Pietro Cicuta
Summary: Cilia density, distribution, and beating frequency are crucial properties of airway epithelial tissues. This article introduces a novel and open-source method for fully characterizing cilia beating frequency and motile cilia coverage in an automated manner without any user intervention. The method successfully differentiates between different coverage densities, identifies small patches of cilia in larger fields of view, and provides a comprehensive characterization of cilia beating frequency in all moving areas.
ROYAL SOCIETY OPEN SCIENCE
(2023)
Editorial Material
Cell Biology
Ivan Olaya, Sean M. Burgess
Summary: A recent study found that a cilium in zebrafish acts as an anchor for the centrosome and is crucial for telomere clustering and germ cell development.
DEVELOPMENTAL CELL
(2022)
Article
Cell Biology
Christine Zimmermann, Nadine Kraemer, Steffi Krauter, Dennis Strand, Elisabeth Sehn, Uwe Wolfrum, Anja Freiwald, Falk Butter, Bodo Plachter
Summary: Viral infections often induce autophagy as a cellular defense mechanism, but herpesviruses have developed strategies to evade autophagic degradation and manipulate autophagy for their benefit. Autophagy machinery proteins and receptors were found to interact with human cytomegalovirus (HCMV) during viral replication and morphogenesis, indicating a role in antiviral defense. However, autophagy was found to be dispensable for secondary HCMV particle envelopment.
Article
Cell Biology
Rachel E. Turn, Joshua Linnert, Eduardo D. Gigante, Uwe Wolfrum, Tamara Caspary, Richard A. Kahn
Summary: ELMOD2 is a GTPase-activating protein with broad specificity for ARF family GTPases, involved in various cellular processes including ciliary morphology and signaling. Functional links exist between ELMOD2, ARL2, and Rootletin, acting together in a pathway to suppress spurious ciliation and maintain centrosome cohesion. These proteins act downstream of TTBK2 and upstream of CP110 to regulate ciliary licensing.
MOLECULAR BIOLOGY OF THE CELL
(2021)
Article
Multidisciplinary Sciences
Deva K. Kusuluri, Baran E. Gueler, Barbara Knapp, Nicola Horn, Karsten Boldt, Marius Ueffing, Gabriela Aust, Uwe Wolfrum
Summary: VLGR1, the largest adhesion G protein-coupled receptor in humans, is associated with diseases like deaf blindness and epilepsy. Research shows that the localization and assembly of VLGR1 in focal adhesions play a critical role in cell spread, migration, and response to mechanical stretch.
Article
Biochemistry & Molecular Biology
Adem Yildirim, Sina Mozaffari-Jovin, Ann-Kathrin Wallisch, Jessica Schafer, Sebastian E. J. Ludwig, Henning Urlaub, Reinhard Luhrmann, Uwe Wolfrum
Summary: The study reveals molecular links between the SANS protein and the spliceosome in catalyzing pre-mRNA splicing in the nucleus. SANS is found in Cajal bodies and nuclear speckles, where it plays a key role in transporting tri-snRNPs and in spliceosome assembly. Depletion of SANS alters the kinetics of spliceosome assembly, leading to accumulation of complex A.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Cell Biology
Rachel E. Turn, Yihan Hu, Skylar Dewees, Narra Devi, Michael P. East, Katherine R. Hardin, Tala Khatib, Joshua Linnert, Uwe Wolfrum, Michael J. Lim, James E. Casanova, Tamara Caspary, Richard A. Kahn
Summary: ELMODs are a family of proteins that regulate the activity of a variety of GTPases. This study investigated the functions of ELMOD1 and ELMOD3 and compared them to the functions of ELMOD2. Deletion of ELMOD1 or ELMOD3 resulted in impaired primary cilium formation and protein trafficking from the Golgi to cilia. These phenotypes were reversed by activating mutant expression of ARL3 or ARL16.
MOLECULAR BIOLOGY OF THE CELL
(2022)
Article
Medicine, Research & Experimental
Sophia Grotz, Jessica Schaefer, Kirsten A. Wunderlich, Zdenka Ellederova, Hannah Auch, Andrea Baehr, Petra Runa-Vochozkova, Janet Fadl, Vanessa Arnold, Taras Ardan, Miroslav Veith, Gianluca Santamaria, Georg Dhom, Wolfgang Hitzl, Barbara Kessler, Christian Eckardt, Joshua Klein, Anna Brymova, Joshua Linnert, Mayuko Kurome, Valeri Zakharchenko, Andrea Fischer, Andreas Blutke, Anna Doering, Stepanka Suchankova, Jiri Popelar, Eduardo Rodriguez-Bocanegra, Julia Dlugaiczyk, Hans Straka, Helen May-Simera, Weiwei Wang, Karl-Ludwig Laugwitz, Luk H. Vandenberghe, Eckhard Wolf, Kerstin Nagel-Wolfrum, Tobias Peters, Jan Motlik, M. Dominik Fischer, Uwe Wolfrum, Nikolai Klymiuk
Summary: This study generated the first translational animal model for Usher syndrome type 1, which exhibits characteristics of hearing loss, vestibular dysfunction, and visual impairment similar to human patients. The research also confirmed the therapeutic potential of gene repair and gene therapy for Usher syndrome through in vitro assessments using primary cells from Usher syndrome pigs or patients.
EMBO MOLECULAR MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Barbara Knapp, Jens Roedig, Heiko Roedig, Jacek Krzysko, Nicola Horn, Baran E. Gueler, Deva Krupakar Kusuluri, Adem Yildirim, Karsten Boldt, Marius Ueffing, Ines Liebscher, Uwe Wolfrum
Summary: In this study, novel protein networks and functional cellular modules associated with VLGR1 were identified using affinity proteomics. The findings provide new insights into the possible functions of VLGR1, related to the development of Usher syndrome, epilepsy, and other neuronal diseases.
Article
Biochemistry & Molecular Biology
Kerstin Nagel-Wolfrum, Benjamin R. Fadl, Mirjana M. Becker, Kirsten A. Wunderlich, Jessica Schaefer, Daniel Sturm, Jacques Fritze, Burcu Guer, Lew Kaplan, Tommaso Andreani, Tobias Goldmann, Matthew Brooks, Margaret R. Starostik, Anagha Lokhande, Melissa Apel, Karl R. Fath, Katarina Stingl, Susanne Kohl, Margaret M. DeAngelis, Ursula Schlotzer-Schrehardt, Ivana K. Kim, Leah A. Owen, Jan M. Vetter, Norbert Pfeiffer, Miguel A. Andrade-Navarro, Antje Grosche, Anand Swaroop, Uwe Wolfrum
Summary: Usher syndrome (USH) is a common genetic disorder causing deaf-blindness. This study explores the role of harmonin protein in the pathophysiology of USH1C in the human eye. The localization and expression of harmonin in various retinal cells are correlated with the clinical phenotype observed in USH1C patients. Additionally, the study shows the potential of using harmonin_a1 transcript isoform for gene therapy treatment in USH1C patients.
HUMAN MOLECULAR GENETICS
(2023)
Article
Cell Biology
Jacek Krzysko, Filip Maciag, Anna Mertens, Baran Enes Gueler, Joshua Linnert, Karsten Boldt, Marius Ueffing, Kerstin Nagel-Wolfrum, Martin Heine, Uwe Wolfrum
Summary: This study reveals the molecular and functional interaction between VLGR1 and MAMs, highlighting the essential role of VLGR1 in the regulation of Ca2+ homeostasis.
Article
Cell Biology
Romy Winkler, Marianne Quaas, Stefan Glasmacher, Uwe Wolfrum, Torsten Thalheim, Joerg Galle, Knut Krohn, Thomas M. Magin, Gabriela Aust
Summary: The expression and function of GPR115 in skin, specifically in epidermal differentiation, has been largely unknown. This study reveals that GPR115 is present in a small subset of keratinocytes in the stratified epidermis, and its expression is delayed in psoriatic skin. Deletion of GPR115 leads to reduced keratinocyte stratification, suggesting its role in epidermal differentiation. Intriguingly, endogenous GPR115 localizes along keratin filaments in a regular pattern, indicating a previously unknown function in regulating epidermal differentiation and keratin expression.
Article
Pharmacology & Pharmacy
Baran E. Gueler, Joshua Linnert, Uwe Wolfrum
Summary: VLGR1/ADGRV1 is a large adhesion G protein-coupled receptor associated with Usher syndrome, epilepsy, and other diseases. It is expressed widely in the CNS, eye, and inner ear. Previous research has shown that VLGR1 plays a role in focal adhesion dynamics and cell migration. This study aimed to elucidate the mechanisms of VLGR1 in focal adhesion turnover.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Joshua Linnert, Baran E. Gueler, Jacek Krzysko, Uwe Wolfrum
Summary: VLGR1/ADGRV1 is the largest known adhesion G protein-coupled receptor, and mutations in VLGR1/ADGRV1 are associated with Usher syndrome and epilepsy. This study identified autophagosomes as potential interacting proteins of VLGR1 and revealed the molecular and functional interaction between VLGR1 and key components of the autophagy process. These findings provide insights into the pathomechanisms underlying human USH and epilepsy related to VLGR1 defects.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Cell Biology
Joshua Linnert, Barbara Knapp, Baran E. Gueler, Karsten Boldt, Marius Ueffing, Uwe Wolfrum
Summary: The human Usher syndrome is characterized by progressive vision and hearing loss. Mutations in ADGRV1 and CIB2 genes are associated with two sub-types of Usher syndrome. The proteins encoded by these two genes belong to distinct protein families. The cellular functions of ADGRV1 and CIB2 are still unclear, but they are found to interact with each other and play a role in primary cilia function.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Cell Biology
Jessica Schaefer, Nicole Wenck, Katharina Janik, Joshua Linnert, Katarina Stingl, Susanne Kohl, Kerstin Nagel-Wolfrum, Uwe Wolfrum
Summary: Human Usher syndrome (USH) is a complex genetic disorder that causes combined deafness and blindness. The underlying mechanisms of the disease, particularly in the eye and retina, are not well understood. This study identifies a role for the scaffold protein harmonin, encoded by the USH1C gene, in regulating the canonical Wnt/beta-catenin signaling pathway. The findings suggest that USH1C/harmonin acts as a suppressor of the pathway, and dysregulation of this pathway may contribute to the development of USH.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Biochemical Research Methods
Baran E. Gueler, Jacek Krzysko, Uwe Wolfrum
Summary: This protocol provides a fast and cost-effective technique for isolating, culturing, and maintaining primary mouse astrocytes at -80% purity levels, which can be used in in vitro studies for migration and focal adhesion dynamics. Additionally, an optimized transfection and manual quantification approach for focal adhesion analysis in fixed and living cells is presented.