scholarly journals A selective autophagy pathway for phase separated endocytic protein deposits

2020 ◽  
Author(s):  
Florian Wilfling ◽  
Chia-Wei Lee ◽  
Philipp Erdmann ◽  
Yumei Zheng ◽  
Stefan Jentsch ◽  
...  
Keyword(s):  
Phase Separation ◽  
Electron Tomography ◽  
List Type ◽  
Selective Autophagy ◽  
Protein Deposits ◽  
Autophagic Degradation ◽  
Cytoplasmic Content ◽  
Membrane Bound ◽  
Autophagy Pathway ◽  
Endocytic Proteins

SummaryAutophagy eliminates cytoplasmic content selected by autophagy receptors, which link cargoes to the membrane bound autophagosomal ubiquitin-like protein Atg8/LC3. Here, we discover a selective autophagy pathway for protein condensates formed by endocytic proteins. In this pathway, the endocytic yeast protein Ede1 functions as a selective autophagy receptor. Distinct domains within Ede1 bind Atg8 and mediate phase separation into condensates. Both properties are necessary for an Ede1-dependent autophagy pathway for endocytic proteins, which differs from regular endocytosis, does not involve other known selective autophagy receptors, but requires the core autophagy machinery. Cryo-electron tomography of Ede1-containing condensates – at the plasma membrane and in autophagic bodies – shows a phase-separated compartment at the beginning and end of the Ede1-mediated selective autophagy pathway. Our data suggest a model for autophagic degradation of membraneless compartments by the action of intrinsic autophagy receptors.HighlightsEde1 is a selective autophagy receptor for aberrant CME protein assembliesAberrant CME assemblies form by liquid-liquid phase separationCore autophagy machinery and Ede1 are important for degradation of CME condensatesUltrastrucural view of a LLPS compartment at the PM and within autophagic bodies

scholarly journals Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2247
Author(s):  
Yi Zhang ◽  
Jiayu Gu ◽  
Qiming Sun
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Phase Separation ◽  
Gene Mutations ◽  
Stress Granules ◽  
Protein Aggregates ◽  
Toxic Protein ◽  
Selective Autophagy ◽  
Dynamic Assembly ◽  
Autophagy Pathway ◽  
Lateral Sclerosis

Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.

scholarly journals A Selective Autophagy Pathway for Phase Separated Endocytic Protein Deposits

2020 ◽  
Author(s):  
Florian Wifling ◽  
Chia-Wei Lee ◽  
Philipp Erdmann ◽  
Yumei Zheng ◽  
Stefan Jentsch ◽  
...  
Keyword(s):  
Selective Autophagy ◽  
Protein Deposits ◽  
Endocytic Protein ◽  
Autophagy Pathway

The F-box E3 ubiquitin ligase BAF1 mediates the degradation of the brassinosteroid-activated transcription factor BES1 through selective autophagy in Arabidopsis

2021 ◽  
Author(s):  
Ping Wang ◽  
Trevor M Nolan ◽  
Natalie M Clark ◽  
Hao Jiang ◽  
Christian Montes-Serey ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Ubiquitin Ligase ◽  
Stress Responses ◽  
E3 Ubiquitin Ligase ◽  
Dependent Manner ◽  
Selective Autophagy ◽  
Sucrose Starvation ◽  
Autophagic Degradation ◽  
Autophagy Pathway

Abstract Brassinosteroids (BRs) regulate plant growth, development, and stress responses by activating the core transcription factor BRI1-EMS-SUPPRESSOR1 (BES1), whose degradation occurs through the proteasome and autophagy pathways. The E3 ubiquitin ligase(s) that modify BES1 for autophagy-mediated degradation remain to be fully defined. Here, we identified an F-box family E3 ubiquitin ligase named BES1-ASSOCIATED F-BOX1 (BAF1) in Arabidopsis thaliana. BAF1 interacts with BES1 and mediates its ubiquitination and degradation. Our genetic data demonstrated that BAF1 inhibits BR signaling in a BES1-dependent manner. Moreover, BAF1 targets BES1 for autophagic degradation in a selective manner. BAF1-triggered selective autophagy of BES1 depends on the ubiquitin binding receptor DOMINANT SUPPRESSOR OF KAR2 (DSK2). Sucrose starvation-induced selective autophagy of BES1, but not bulk autophagy, was significantly compromised in baf1 mutant and BAF1-ΔF (BAF1 F-box decoy) overexpression plants, but clearly increased by BAF1 overexpression. The baf1 and BAF1-ΔF overexpression plants had increased BR-regulated growth but were sensitive to long-term sucrose starvation, while BAF1 overexpression plants had decreased BR-regulated growth but were highly tolerant of sucrose starvation. Our results not only established BAF1 as an E3 ubiquitin ligase that targets BES1 for degradation through selective autophagy pathway, but also revealed a mechanism for plants to reduce growth during sucrose starvation.

scholarly journals A Selective Autophagy Pathway for Phase-Separated Endocytic Protein Deposits

2020 ◽  
Vol 80 (5) ◽  
pp. 764-778.e7 ◽  
Author(s):  
Florian Wilfling ◽  
Chia-Wei Lee ◽  
Philipp S. Erdmann ◽  
Yumei Zheng ◽  
Dawafuti Sherpa ◽  
...  
Keyword(s):  
Selective Autophagy ◽  
Protein Deposits ◽  
Endocytic Protein ◽  
Autophagy Pathway

scholarly journals The influence of membrane bound proteins on phase separation and coarsening in cell membranes

2012 ◽  
Vol 14 (42) ◽  
pp. 14509 ◽  
Author(s):  
Thomas Witkowski ◽  
Rainer Backofen ◽  
Axel Voigt
Keyword(s):  
Phase Separation ◽  
Cell Membranes ◽  
Membrane Bound

scholarly journals NBR1 directly promotes the formation of p62 – ubiquitin condensates via its PB1 and UBA domains

2020 ◽  
Author(s):  
Adriana Savova ◽  
Julia Romanov ◽  
Sascha Martens
Keyword(s):  
Phase Separation ◽  
Wild Type ◽  
Selective Autophagy ◽  
Ubiquitinated Proteins ◽  
Cargo Receptor ◽  
Condensate Formation ◽  
Uba Domain ◽  
Reconstituted System ◽  
Pb1 Domain

SummarySelective autophagy removes harmful intracellular structures such as ubiquitinated, aggregated proteins ensuring cellular homeostasis. This is achieved by the encapsulation of this cargo material within autophagosomes. The cargo receptor p62/SQSTM1 mediates the phase separation of ubiquitinated proteins into condensates, which subsequently become targets for the autophagy machinery. NBR1, another cargo receptor, is a crucial regulator of condensate formation. The mechanisms of the interplay between p62 and NBR1 are not well understood. Employing a fully reconstituted system we show that two domains of NBR1, the PB1 domain which binds to p62 and the UBA domain which binds to ubiquitin, are required to promote p62-ubiquitin condensate formation. In cells, acute depletion of endogenous NBR1 reduces formation of p62 condensates, a phenotype that can be rescued by re-expression of wild-type NBR1, but not PB1 or UBA domain mutants. Our results provide mechanistic insights into the role of NBR1 in selective autophagy.

scholarly journals Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

2019 ◽  
Author(s):  
Ameya P. Jalihal ◽  
Sethuramasundaram Pitchiaya ◽  
Lanbo Xiao ◽  
Pushpinder Bawa ◽  
Xia Jiang ◽  
...  
Keyword(s):  
Phase Separation ◽  
Cell Volume ◽  
Volume Change ◽  
Mammalian Cells ◽  
Internal State ◽  
Transcription Termination ◽  
Cell Types ◽  
List Type ◽  
Molecular Crowding ◽  
Minimal Impact

SUMMARYProcessing bodies (PBs) and stress granules (SGs) are prominent examples of sub-cellular, membrane-less compartments that are observed under physiological and stress conditions, respectively. We observe that the trimeric PB protein DCP1A rapidly (within ∼10 s) phase-separates in mammalian cells during hyperosmotic stress and dissolves upon isosmotic rescue (over ∼100 s) with minimal impact on cell viability even after multiple cycles of osmotic perturbation. Strikingly, this rapid intracellular hyperosmotic phase separation (HOPS) correlates with the degree of cell volume compression, distinct from SG assembly, and is exhibited broadly by homo-multimeric (valency ≥ 2) proteins across several cell types. Notably, HOPS sequesters pre-mRNA cleavage factor components from actively transcribing genomic loci, providing a mechanism for hyperosmolarity-induced global impairment of transcription termination. Together, our data suggest that the multimeric proteome rapidly responds to changes in hydration and molecular crowding, revealing an unexpected mode of globally programmed phase separation and sequestration that adapts the cell to volume change.GRAPHICAL ABSTRACTIN BRIEFCells constantly experience osmotic variation. These external changes lead to changes in cell volume, and consequently the internal state of molecular crowding. Here, Jalihal and Pitchiaya et al. show that multimeric proteins respond rapidly to such cellular changes by undergoing rapid and reversible phase separation.HIGHLIGHTSDCP1A undergoes rapid and reversible hyperosmotic phase separation (HOPS)HOPS of DCP1A depends on its trimerization domainSelf-interacting multivalent proteins (valency ≥ 2) undergo HOPSHOPS of CPSF6 explains transcription termination defects during osmotic stress

Mechanisms of Selective Autophagy

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Trond Lamark ◽  
Terje Johansen
Keyword(s):  
Annual Review ◽  
Publication Date ◽  
Sequence Motifs ◽  
Substrate Selection ◽  
Lysosomal Degradation ◽  
Autophagosome Formation ◽  
Selective Autophagy ◽  
Late Endosomes ◽  
Membrane Bound ◽  
Unifying Principles

Selective autophagy is the lysosomal degradation of specific intracellular components sequestered into autophagosomes, late endosomes, or lysosomes through the activity of selective autophagy receptors (SARs). SARs interact with autophagy-related (ATG)8 family proteins via sequence motifs called LC3-interacting region (LIR) motifs in vertebrates and Atg8-interacting motifs (AIMs) in yeast and plants. SARs can be divided into two broad groups: soluble or membrane bound. Cargo or substrate selection may be independent or dependent of ubiquitin labeling of the cargo. In this review, we discuss mechanisms of mammalian selective autophagy with a focus on the unifying principles employed in substrate recognition, interaction with the forming autophagosome via LIR-ATG8 interactions, and the recruitment of core autophagy components for efficient autophagosome formation on the substrate. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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