Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport DOI Creative Commons
Marianna Leonzino, Karin M. Reinisch, Pietro De Camilli

et al.

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Journal Year: 2021, Volume and Issue: 1866(10), P. 159003 - 159003

Published: July 1, 2021

The occurrence of protein mediated lipid transfer between intracellular membranes has been known since the late 1960's. Since these early discoveries, numerous proteins responsible for such transport, which often act at membrane contact sites, have identified. Typically, they comprise a harboring module thought to shuttle back and forth two adjacent bilayers. Recently, however, studies chorein domain family, includes VPS13 ATG2, led identification novel mechanism transport organelles in eukaryotic cells by rod-like bridge with hydrophobic groove through lipids can slide. This is ideally suited bulk bilayer promote growth. Here we describe how discovery this new mechanism, summarize properties roles proteins, discuss their dysfunction may lead disease.

Language: Английский

Autophagy genes in biology and disease DOI Open Access
Hayashi Yamamoto, Sidi Zhang, Noboru Mizushima

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(6), P. 382 - 400

Published: Jan. 12, 2023

Language: Английский

Citations

365
Autophagy in metabolic disease and ageing DOI
Munehiro Kitada, Daisuke Koya

Nature Reviews Endocrinology, Journal Year: 2021, Volume and Issue: 17(11), P. 647 - 661

Published: Sept. 10, 2021

Language: Английский

Citations

287
Mechanisms of Selective Autophagy DOI
Trond Lamark, Terje Johansen

Annual Review of Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 37(1), P. 143 - 169

Published: June 21, 2021

Selective autophagy is the lysosomal degradation of specific intracellular components sequestered into autophagosomes, late endosomes, or lysosomes through activity selective receptors (SARs). SARs interact with autophagy-related (ATG)8 family proteins via sequence motifs called LC3-interacting region (LIR) in vertebrates and Atg8-interacting (AIMs) yeast plants. can be divided two broad groups: soluble membrane bound. Cargo substrate selection may independent dependent ubiquitin labeling cargo. In this review, we discuss mechanisms mammalian a focus on unifying principles employed recognition, interaction forming autophagosome LIR-ATG8 interactions, recruitment core for efficient formation substrate.

Language: Английский

Citations

285
A model for a partnership of lipid transfer proteins and scramblases in membrane expansion and organelle biogenesis DOI Creative Commons
Alireza Ghanbarpour, Diana P. Valverde, Thomas J. Melia

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(16)

Published: April 13, 2021

The autophagy protein ATG2, proposed to transfer bulk lipid from the endoplasmic reticulum (ER) during autophagosome biogenesis, interacts with ER residents TMEM41B and VMP1 ATG9, in Golgi-derived vesicles that initiate formation. In vitro assays reveal TMEM41B, VMP1, ATG9 as scramblases. We propose a model wherein membrane expansion results partnership of protein, moving lipids between cytosolic leaflets apposed organelles, scramblases reequilibrate donor acceptor organelle membranes are depleted or augmented. implicated broadly homeostasis dynamics processes which their scrambling activities likely key.

Language: Английский

Citations

193
Autophagosome biogenesis comes out of the black box DOI
Chunmei Chang, Liv Jensen, James H. Hurley

et al.

Nature Cell Biology, Journal Year: 2021, Volume and Issue: 23(5), P. 450 - 456

Published: April 26, 2021

Language: Английский

Citations

135
Mechanisms of nonvesicular lipid transport DOI Creative Commons
Karin M. Reinisch, William A. Prinz

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(3)

Published: Feb. 19, 2021

We have long known that lipids traffic between cellular membranes via vesicles but only recently appreciated the role of nonvesicular lipid transport. Nonvesicular transport can be high volume, supporting biogenesis rapidly expanding membranes, or more targeted and precise, allowing cells to alter levels specific in membranes. Most such probably occurs at membrane contact sites, where organelles are closely apposed, requires proteins (LTPs), which solubilize shield them from aqueous phase during their Some LTPs cup like shuttle monomers Others form conduits flow This review describes what we know about transfer mechanisms while also identifying many remaining unknowns: How do facilitate movement into require accessory for efficient vivo, how is directionality determined?

Language: Английский

Citations

129
ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum DOI Creative Commons
Fulvio Reggiori, Maurizio Molinari

Physiological Reviews, Journal Year: 2022, Volume and Issue: 102(3), P. 1393 - 1448

Published: Feb. 21, 2022

ER-phagy (reticulophagy) defines the degradation of portions endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part self-digestion (i.e., autophagic) programs recycling cytoplasmic material and organelles, which rapidly mobilize metabolites in cells confronted with nutrient shortage. Moreover, selective clearance ER subdomains participates control size activity during stress, reestablishment homeostasis after stress resolution, removal parts aberrant potentially cytotoxic has been segregated. relies on individual and/or concerted activation receptors, peripheral integral membrane proteins that share presence LC3/Atg8-binding motifs their cytosolic domains. involves physical separation from bulk network delivery to endolysosomal/vacuolar catabolic district. This last step accomplished by a variety mechanisms including macro-ER-phagy (in fragments are sequestered double-membrane autophagosomes eventually fuse lysosomes/vacuoles), micro-ER-phagy directly engulfed endosomes/lysosomes/vacuoles), direct fusion ER-derived vesicles lysosomes/vacuoles. dysfunctional specific human diseases, its regulators subverted pathogens, highlighting crucial role for cell organism life.

Language: Английский

Citations

111
Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites DOI Creative Commons

Qiaoxia Zheng,

Yong Chen, Di Chen

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(22), P. 4082 - 4098.e22

Published: Oct. 1, 2022

Highlights•Autophagy induction elicits Ca2+ transients on the outer surface of ER membrane•EPG-4/EI24 controls amplitude, frequency, and duration transients•Ca2+ induce formation fusion-prone, liquid-like FIP200 puncta•ATG9 modulates phase separation organization puncta ERSummaryThe mechanism that initiates autophagosome in multicellular organisms is elusive. Here, we showed autophagy stimuli trigger membrane, whose are controlled by metazoan-specific transmembrane protein EPG-4/EI24. Persistent transients/oscillations cytosolic EI24-depleted cells cause accumulation initiation complexes ER. This defect suppressed attenuating transients. Multi-modal SIM analysis revealed dynamic fusion-prone puncta. Starvation-induced lysosomes also further move to Multiple ER, association depends proteins VAPA/B ATL2/3, assemble into sites. Thus, crucial for triggering specify sites metazoans.Graphical abstract

Language: Английский

Citations

108
ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation DOI Creative Commons
Alexander R. van Vliet, George N. Chiduza, Sarah Maslen

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(22), P. 4324 - 4339.e8

Published: Nov. 1, 2022

ATG9A and ATG2A are essential core members of the autophagy machinery. is a lipid scramblase that allows equilibration lipids across membrane bilayer, whereas facilitates flow between tethered membranes. Although both have been functionally linked during formation autophagosomes, molecular details consequences their interaction remain unclear. By combining data from peptide arrays, crosslinking, hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, we propose model ATG9A-2A complex. Using this integrative structure modeling approach, identify several interfaces mediating would allow direct transfer into lipid-binding perpendicular branch ATG9A. Mutational analyses combined functional activity assays demonstrate importance for autophagy, thereby shedding light on protein complex at heart autophagy.

Language: Английский

Citations

91
Orchestration of selective autophagy by cargo receptors DOI Creative Commons
Elias Adriaenssens, Luca Ferrari, Sascha Martens

et al.

Current Biology, Journal Year: 2022, Volume and Issue: 32(24), P. R1357 - R1371

Published: Dec. 1, 2022

Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for degradation such cargo This is achieved by sequestration within double-membrane vesicles termed autophagosomes, which form de novo around subsequently deliver their content to lysosomes degradation. The importance selective exemplified various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia. It has become evident that receptors are acting as Swiss army knives recognizing cargo, orchestrating recruitment machinery autophagosome biogenesis, closely aligning membrane cargo. Furthermore, sequester ubiquitinated proteins into larger condensates upstream induction. Here, we review recent insights mechanisms action focusing on roles sequestosome-like misfolded, mitochondria. We also highlight at steps function result accumulation harmful material how knowledge may guide design future therapies.

Language: Английский

Citations

77