A DNM2 Centronuclear Myopathy Mutation Reveals a Link between Recycling Endosome Scission and Autophagy.

Autophagy involves engulfment of cytoplasmic contents by double-membraned autophagosomes, which ultimately fuse with lysosomes to enable degradation of their substrates. We recently proposed that the tubular-vesicular recycling endosome membranes were a core platform on which the critical early events of autophagosome formation occurred, including LC3-membrane conjugation to autophagic precursors. Here, we report that the release of autophagosome precursors from recycling endosomes is mediated by DNM2-dependent scission of these tubules. This process is regulated by DNM2 binding to LC3 and is increased by autophagy-inducing stimuli. This scission is defective in cells expressing a centronuclear-myopathy-causing DNM2 mutant. This mutant has an unusual mechanism as it depletes normal-functioning DNM2 from autophagosome formation sites on recycling endosomes by causing increased binding to an alternative plasma membrane partner, ITSN1. This "scission" step is, thus, critical for autophagosome formation, is defective in a human disease, and influences the way we consider how autophagosomes are formed

Mechanism of eIF6 release from the nascent 60S ribosomal subunit.

SBDS protein (deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits. However, the mechanism is completely unknown. Here, we present cryo-EM structures of human SBDS and SBDS-EFL1 bound to Dictyostelium discoideum 60S ribosomal subunits with and without endogenous eIF6. SBDS assesses the integrity of the peptidyl (P) site, bridging uL16 (mutated in T-cell acute lymphoblastic leukemia) with uL11 at the P-stalk base and the sarcin-ricin loop. Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. Our data reveal the conserved mechanism of eIF6 release, which is corrupted in both inherited and sporadic leukemias.Supported by a Federation of European Biochemical Societies Long term Fellowship (to FW), Specialist Programme from Bloodwise [12048] (AJW), the Medical Research Council [MC_U105161083] (AJW) and [U105115237] (RRK), Wellcome Trust strategic award to the Cambridge Institute for Medal Research [100140], Tesni Parry Trust (AJW), Ted’s Gang (AJW) and the Cambridge NIHR Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nsmb.311

How Does One Learn? Is There a Method?

The definition of learning is to gain or acquire knowledge of or skill in (something) by study, experience, or being taught. We discuss here the different methods of learning in traditional and modern societies. We conclude that what we have learned to date is negligible compare to what remains to learn

How Does One Learn? Is There a Method?

The definition of learning is to gain or acquire knowledge of or skill in (something) by study, experience, or being taught. We discuss here the different methods of learning in traditional and modern societies. We conclude that what we have learned to date is negligible compare to what remains to learn

Multi-dimensional nuclear magnetic resonance studies of the dynamics and mechanism of FBP-aldolase

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Privacy, Education and Human Dignity

Access to knowledge for everyone in the increasingly-interconnected society has been a tool for democracy. We discuss here the dangers of a world online and the growing concerns about state surveillance, security, privacy and exploitation. We discuss our right to protect our individual freedom. We conclude that privacy is a fundamental Human Rights in order to guarantee human dignity and freedom

Covid Tracking Apps, Over Reliance on Technology, Bias and Unfairness

Various contact tracing apps tracking the spread of the pandemic were issued in different countries. Mainly based on two technologies, centralised with more control by the governments or decentralised controlled by the Apple or Google Android mobile phone systems. In this paper, we will discuss the advantages and disadvantages of the different systems, as well as their potential dangers

eIF6 rebinding dynamically couples ribosome maturation and translation.

Protein synthesis is a cyclical process consisting of translation initiation, elongation, termination and ribosome recycling. The release factors SBDS and EFL1-both mutated in the leukemia predisposition disorder Shwachman-Diamond syndrome - license entry of nascent 60S ribosomal subunits into active translation by evicting the anti-association factor eIF6 from the 60S intersubunit face. We find that in mammalian cells, eIF6 holds all free cytoplasmic 60S subunits in a translationally inactive state and that SBDS and EFL1 are the minimal components required to recycle these 60S subunits back into additional rounds of translation by evicting eIF6. Increasing the dose of eIF6 in mice in vivo impairs terminal erythropoiesis by sequestering post-termination 60S subunits in the cytoplasm, disrupting subunit joining and attenuating global protein synthesis. These data reveal that ribosome maturation and recycling are dynamically coupled by a mechanism that is disrupted in an inherited leukemia predisposition disorder

VAMP2 regulates phase separation of α-synuclein

Alpha-synuclein (aSYN), a pivotal synaptic protein implicated in synucleinopathies like Parkinson’s disease (PD) and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates aSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and aSYN’s C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on aSYN lipid membrane binding. Our results delineate a regulatory mechanism for aSYN phase separation in cells. Furthermore, we show that aSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology