A selective autophagy pathway that degrades gluconeogenic enzymes during catabolite inactivation

Macro-autophagy is an essential cellular process involved in degradation of aberrant organelles and proteins. Initially proposed to be a ‘bulk’ degradation pathway, a more nuanced appreciation of selective autophagy pathways has emerged in recent years. The discovery of a glycogen-selective autophagy pathway (‘glycophagy’) has highlighted the importance of autophagy in regulating cellular metabolic homeostasis and identified a novel non-canonical major pathway of glycogen flux. The field of glycogen autophagy research is at an early evolutionary stage, but already it is clear that the implications of these discoveries are far-reaching and provide scope for multi-disciplinary investigations into the role of glycophagy in health and disease. With potential cognate protein partners identified, the opportunities for targeted intervention have become viable. Here we review the current evidence relating to specific protein mediators involved in glycophagy, and highlight areas of uncertainty that provide opportunity for further investigation.

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Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to control Mycobacterium tuberculosis infection in macrophages

10.1101/2020.06.30.180877 ◽

2020 ◽

Author(s):

Samantha L. Bell ◽

Kayla L. Lopez ◽

Jeffery S. Cox ◽

Kristin L. Patrick ◽

Robert O. Watson

Keyword(s):

Mycobacterium Tuberculosis ◽

Specific Interaction ◽

Secretion System ◽

Autophagosome Formation ◽

Mycobacterium Tuberculosis Infection ◽

Selective Autophagy ◽

Galectin 3 ◽

Autophagy Pathway ◽

Sense And Respond ◽

Phagosomal Membrane

ABSTRACTMycobacterium tuberculosis (Mtb) infects a quarter of the world and causes the deadliest infectious disease worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell and establish a replicative niche. We have previously shown the ESX-1 secretion system permeabilizes the Mtb-containing phagosome and that a population (~30%) of intracellular Mtb are recognized within the cytosol, tagged with ubiquitin, and targeted to the selective autophagy pathway. Despite the importance of selective autophagy in controlling infection, the mechanisms through which macrophages sense and respond to damaged Mtb-containing phagosomes remains unclear. Here, we demonstrate that several cytosolic glycan-binding proteins, known as galectins, recognize Mtb-containing phagosomes. We found that galectins-3, -8, and -9 are all recruited to the same Mtb population that colocalizes with selective autophagy markers like ubiquitin, p62, and LC3, which indicates Mtb damages its phagosomal membrane such that cytosolic host sensors can recognize danger signals in the lumen. To determine which galectins are required for controlling Mtb replication in macrophages, we generated CRISPR/Cas9 knockout macrophages lacking individual or multiple galectins and found that galectin-8-/- and galectin-3/8/9-/- knockout macrophages were similarly defective in targeting Mtb to selective autophagy and controlling replication, suggesting galectin-8 plays a privileged role in anti-Mtb autophagy. In investigating this specificity, we identified a novel and specific interaction between galectin-8 and TAX1BP1, one of several autophagy adaptors that bridges cargo and LC3 during the course of autophagosome formation, and this galectin-8/TAX1BP1 interaction was necessary to efficiently target Mtb to selective autophagy. Remarkably, overexpressing individual galectins increased targeting of Mtb to antibacterial autophagy and limited Mtb replication. Taken together, these data imply that galectins recognize damaged Mtb-containing phagosomes, recruit downstream autophagy machinery, and may represent promising targets for host-directed therapeutics to treat Mtb.

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Molecular and structural mechanisms of ZZ domain-mediated cargo recognition by autophagy receptor Nbr1

10.1101/2021.02.07.430097 ◽

2021 ◽

Author(s):

Ying-Ying Wang ◽

Jianxiu Zhang ◽

Xiao-Man Liu ◽

Meng-Qiu Dong ◽

Keqiong Ye ◽

...

Keyword(s):

High Resolution ◽

Fission Yeast ◽

Protein Interactions ◽

Specific Protein ◽

Structural Basis ◽

Protein Protein Interactions ◽

Selective Autophagy ◽

Specific Manner ◽

Autophagy Pathway ◽

Structural Mechanisms

AbstractIn selective autophagy, cargo selectivity is determined by autophagy receptors. However, it remains scarcely understood how autophagy receptors recognize specific protein cargos. In the fission yeast Schizosaccharomyces pombe, a selective autophagy pathway termed Nbr1-mediated vacuolar targeting (NVT) employs Nbr1, an autophagy receptor conserved across eukaryotes including humans, to target cytosolic hydrolases into the vacuole. Here, we identify two new NVT cargos, the mannosidase Ams1 and the aminopeptidase Ape4, that bind competitively to the first ZZ domain of Nbr1 (Nbr1-ZZ1). High-resolution cryo-EM analyses reveal how a single ZZ domain recognizes two distinct protein cargos. Nbr1-ZZ1 not only recognizes the N-termini of cargos via a conserved acidic pocket, similar to other characterized ZZ domains, but also engages additional parts of cargos in a cargo-specific manner. Our findings unveil a single-domain bispecific mechanism of autophagy cargo recognition, elucidate its underlying structural basis, and expand the understanding of ZZ domain-mediated protein-protein interactions.

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Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis

Cells ◽

10.3390/cells10092247 ◽

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.

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Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy

eLife ◽

10.7554/elife.25555 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 136

Author(s):

Paolo Grumati ◽

Giulio Morozzi ◽

Soraya Hölper ◽

Muriel Mari ◽

Marie-Lena IE Harwardt ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Biological Activity ◽

Mammalian Cells ◽

The Other ◽

Unique Function ◽

Specific Receptor ◽

Selective Autophagy ◽

Specific Receptors ◽

Autophagy Pathway ◽

Tubular Endoplasmic Reticulum

The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy.

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Zymophagy, a Novel Selective Autophagy Pathway Mediated by VMP1-USP9x-p62, Prevents Pancreatic Cell Death

Journal of Biological Chemistry ◽

10.1074/jbc.m110.197301 ◽

2010 ◽

Vol 286 (10) ◽

pp. 8308-8324 ◽

Cited By ~ 127

Author(s):

Daniel Grasso ◽

Alejandro Ropolo ◽

Andrea Lo Ré ◽

Verónica Boggio ◽

María I. Molejón ◽

...

Keyword(s):

Cell Death ◽

Pancreatic Cell ◽

Selective Autophagy ◽

Autophagy Pathway

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A Tecpr1-Dependent Selective Autophagy Pathway Targets Bacterial Pathogens

Cell Host & Microbe ◽

10.1016/j.chom.2011.04.010 ◽

2011 ◽

Vol 9 (5) ◽

pp. 376-389 ◽

Cited By ~ 103

Author(s):

Michinaga Ogawa ◽

Yuko Yoshikawa ◽

Taira Kobayashi ◽

Hitomi Mimuro ◽

Makoto Fukumatsu ◽

...

Keyword(s):

Bacterial Pathogens ◽

Selective Autophagy ◽

Autophagy Pathway

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Regulation of ER-phagy by a Ypt/Rab GTPase module

Molecular Biology of the Cell ◽

10.1091/mbc.e13-05-0269 ◽

2013 ◽

Vol 24 (19) ◽

pp. 3133-3144 ◽

Cited By ~ 39

Author(s):

Zhanna Lipatova ◽

Ankur H. Shah ◽

Jane J. Kim ◽

Jonathan W. Mulholland ◽

Nava Segev

Keyword(s):

Endoplasmic Reticulum ◽

Membrane Trafficking ◽

Eukaryotic Cells ◽

Rab Gtpase ◽

Rab Gtpases ◽

Cellular Compartment ◽

Selective Autophagy ◽

Downstream Effector ◽

Golgi Transport ◽

Autophagy Pathway

Accumulation of misfolded proteins on intracellular membranes has been implicated in neurodegenerative diseases. One cellular pathway that clears such aggregates is endoplasmic reticulum autophagy (ER-phagy), a selective autophagy pathway that delivers excess ER to the lysosome for degradation. Not much is known about the regulation of ER-phagy. The conserved Ypt/Rab GTPases regulate all membrane trafficking events in eukaryotic cells. We recently showed that a Ypt module, consisting of Ypt1 and autophagy-specific upstream activator and downstream effector, regulates the onset of selective autophagy in yeast. Here we show that this module acts at the ER. Autophagy-specific mutations in its components cause accumulation of excess membrane proteins on aberrant ER structures and induction of ER stress. This accumulation is due to a block in transport of these membranes to the lysosome, where they are normally cleared. These findings establish a role for an autophagy-specific Ypt1 module in the regulation of ER-phagy. Moreover, because Ypt1 is a known key regulator of ER-to-Golgi transport, these findings establish a second role for Ypt1 at the ER. We therefore propose that individual Ypt/Rabs, in the context of distinct modules, can coordinate alternative trafficking steps from one cellular compartment to different destinations.

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