6 research outputs found
BAFF controls B cell metabolic fitness through a PKCβ- and Akt-dependent mechanism
B cell life depends critically on the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF). Lack of BAFF signaling leads to B cell death and immunodeficiency. Excessive BAFF signaling promotes lupus-like autoimmunity. Despite the great importance of BAFF to B cell biology, its signaling mechanism is not well characterized. We show that BAFF initiates signaling and transcriptional programs, which support B cell survival, metabolic fitness, and readiness for antigen-induced proliferation. We further identify a BAFF-specific protein kinase C β–Akt signaling axis, which provides a connection between BAFF and generic growth factor–induced cellular responses
Analysis of signaling mechanisms essential to mature B cell viability
Die Langlebigkeit reifer periphärer B Zellen ist abhängig von mindestens zwei Überlebenssignalen, einem tonischen Signal, welches vom B Zellrezeptor ausgeht und dem Zytokin B Zell aktivierender Faktor der TNF-Familie (BAFF). BAFF fördert nicht nur das Überleben von reifen B Zellen, sondern kontrolliert auch deren Funktionstüchtigkeit, indem es vielschichtige physiologische Prozesse wie Zellwachstum und –metabolismus, Energiehaushalt und Eintritt in den Zellzyklus reguliert. Zwei BAFF-induzierte molekulare Mechanismen, zum einen die Aktivierung des Akt Signaltransduktionsweges sowie die erhöhte Expression der onkogenen kinase Pim-2 zum anderen, führen zu Veränderungen in Effektorproteinen welche in der Lage sind diese physiologischen Zellveränderungen auszulösen. Die BAFF-induzierte Aktivierung von Akt hängt von der klassischen Proteinkinase C (PKC) beta ab und sowohl PKC beta-defiziente B Zellen als auch Mäuse zeigen Anzeichen von Unsensitivität gegenüber BAFF-Stimulation. Die Proteintyrosinkinase Syk spielt eine Rolle während der frühen B Zellentwicklung und wird in reifen B Zellen durch Stimulation des B Zellrezeptors aktiviert. Induzierbare Inaktivierung von Syk in Mäusen führt zum Verschwinden reifer B Zellen aus den periphären lymphoiden Organen, was auf eine unverzichtbare Funktion von Syk in der Vermittlung des tonischen B Zellrezeptorsignals schliessen läßt.The maintenance of mature peripheral B cells depends on at least two survival cues, tonic signaling from the B cell receptor (BCR) complex and the extracellular cytokine B cell activating factor of the TNF family (BAFF). In addition to enhancing viability, BAFF controls the functional efficiency of the peripheral B cell pool by regulating complex physiological processes including cell growth, metabolism, energy homeostasis and entry into the cell cycle. BAFF-mediated induction of two molecular mechanisms, namely activation of the Akt signal transduction pathway and upregulation of the oncogenic kinase Pim-2 results in the modification of effector proteins including transcription factors and regulators of protein synthesis which are capable of executing the observed cellular physiological changes. The classic protein kinase C beta is instrumental in BAFF-induced Akt-activation and PKC beta-deficient B cells and mice show signs of partial refractiveness to BAFF. The protein tyrosine kinase Syk plays a role in early B cell development and is activated in mature B cells by immunogenic BCR-stimulation. Inducible ablation of Syk in mice results in the loss mature B cells from the peripheral lymphoid organs and reveals an indispensable function for Syk in tonic BCR survival signaling
Architecture of the cytoplasmic face of the nuclear pore
Quantitative docking of crystal structures into low resolution human cryo-ET and X. laevis cryo-EM maps of the nuclear pore complex cytoplasmic face.Related Publication:
Architecture of the cytoplasmic face of the nuclear pore
Bley, Christopher Caltech
Nie, Si Caltech
Mobbs, George Caltech
Petrovic, Stefan Caltech
Gres, Anna Caltech
Liu, Xiaoyu Caltech
Mukherjee, Somnath The University of Chicago
Harvey, Sho Caltech
Huber, Ferdinand Caltech
Lin, Daniel Caltech
Brown, Bonnie Caltech
Tang, Aaron Caltech
Rundlet, Emily Caltech
Correia, Ana Caltech
Chen, Shane National Institute of Child Health and Human Development
Regmi, Saroj National Institute of Child Health and Human Development
Jette, Claudia Caltech
Stevens, Taylor Caltech
Dasso, Mary National Institute of Child Health and Human Development
Patke, Alina Caltech
Palazzo, Alexander University of Toronto
Kossiakoff, Anthony The University of Chicago
Hoelz, Andre Caltech
Science
2022-06-10
https://doi.org/10.1126/science.abm9129
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