Small differences make a big impact: Structural insights into the differential function of the 2 Atg8 homologs in<i>C. elegans</i>

Wu, Fan; Wang, Peng; Shen, Yujun; Noda, Nobuo N.; Zhang, Hong

doi:10.1080/15548627.2015.1137413

Cited by 5 publications

(3 citation statements)

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“…LGG-1 and LGG-2 were found to show structural and functional similarity to GABARAP and LC3 subfamily, respectively [41,42]. However, in many plants, there can be more than 6 Atg8 isoforms [43].…”

Section: Role Of Evolutionary Constraintsmentioning

confidence: 99%

Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations

et al. 2019

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Autophagy is a conserved adaptive cellular pathway essential to maintain a variety of physiological functions. Core components of this machinery are the six human Atg8 orthologs that initiate formation of appropriate protein complexes. While these proteins are routinely used as indicators of autophagic flux, it is presently not possible to discern their individual biological functions due to our inability to predict specific binding partners. In our attempts towards determining downstream effector functions, we developed a computational pipeline to define structural determinants of human Atg8 family members that dictate functional diversity. We found a clear evolutionary separation between human LC3 and GABARAP subfamilies and also defined a novel sequence motif responsible for their specificity. By analyzing known protein structures, we observed that functional modules or microclusters reveal a pattern of intramolecular network, including distinct hydrogen bonding of key residues (F52/Y49; a subset of HP2) that may directly modulate their interaction preferences. Multiple molecular dynamics simulations were performed to characterize how these proteins interact with a common protein binding partner, PLEKHM1. Our analysis showed remarkable differences in binding modes via intrinsic protein dynamics, with PLEKHM1-bound GABARAP complexes showing less fluctuations and higher number of contacts. We further mapped 373 genomic variations and demonstrated that distinct cancer-related mutations are likely to lead to significant structural changes. Our findings present a quantitative framework to establish factors underlying exquisite specificity of human Atg8 proteins, and thus facilitate the design of precise modulators.

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Section: Role Of Evolutionary Constraintsmentioning

confidence: 99%

Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations

et al. 2019

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“…To examine whether the incorporation of autophagosomes into phagosomes affects the clearance of the engulfed apoptotic cells, we first quantified whether, in mutants of genes essential for the biogenesis of autophagosomes, apoptotic cells were un-degraded and thus persisted in embryos. In addition to the atg-7, atg-9, atg-13, and epg-8 mutants characterized above, we also characterized lossof-function mutants of lgg-1 and lgg-2, and of atg-3, whose gene product is essential for the conjugation of a phosphatidylethanolamine (PE) tail to the LC3 family proteins [33,41], of atg-2 and atg-18, whose gene products function together with ATG-9 in the expansion of phagophore [38], and of unc-51, which LGG-1 and LGG-2 act in engulfing cells, and together they define three subpopulations of autophagosomes that are incorporated into phagosomes…”

Section: Autophagosomes Facilitate the Degradation Of Apoptotic Cells Inside Phagosomesmentioning

confidence: 99%

Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells in Caenorhabditis elegans

Peña-Ramos

Chiao

et al. 2022

eLife

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Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematode Caenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant defects in the degradation of apoptotic cells, demonstrating the importance of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, the adaptor protein CED-6, and the large GTPase dynamin (DYN-1) promotes the recruitment of autophagosomes to phagosomes. Moreover, the subsequent fusion of autophagosomes with phagosomes requires the functions of the small GTPase RAB-7 and the HOPS complex components. Further observations suggest that autophagosomes provide apoptotic cell-degradation activities in addition to and in parallel of lysosomes. Our findings reveal that, unlike the single-membrane, LC3-associated phagocytosis (LAP) vesicles reported for mammalian phagocytes, the canonical double-membrane autophagosomes facilitate the clearance of C. elegans apoptotic cells. These findings add autophagosomes to the collection of intracellular organelles that contribute to phagosome maturation, identify novel crosstalk between the autophagy and phagosome maturation pathways, and discover the upstream signaling molecules that initiate this crosstalk.

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“…To examine whether the incorporation of autophagosomes into phagosomes affects the clearance of the engulfed apoptotic cells, we first quantified whether, in mutants of genes essential for the biogenesis of autophagosomes, apoptotic cells were un-degraded and persistent in embryos. In addition to the atg-7, atg-9, atg-13, and epg-8 mutants characterized above, we also characterized loss-offunction mutants of lgg-1 and lgg-2, and of atg-3, whose gene product is essential for the conjugation of a PE tail to the LC3 family proteins [32,38], of atg-2 and atg-18, whose gene products function together with ATG-9 in the expansion of phagophore [37], and of unc-51, which encodes a C. elegans homolog of ULK1, an autophagic protein kinase [37]. To determine whether the lack of autophagosomes impairs the engulfment or degradation of cell corpses, we monitored the formation and degradation of phagosomes containing apoptotic cells C1, C2, and C3 (Fig 1B) in wild-type, atg-7, and lgg mutant embryos in real-time using established protocol (Materials and Methods) [24,27].…”

Section: Autophagosomes Facilitate the Degradation Of Apoptotic Cells Inside Phagosomesmentioning

confidence: 99%

Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells inCaenorhabditis elegans

Peña-Ramos

Chiao

et al. 2021

Preprint

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Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. In the nematode Caenorhabditis elegans, 113 somatic cells undergo apoptosis during embryogenesis and are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells in C. elegans embryos using a real-time imaging technique. Specifically, double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner membrane to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant delays in the degradation of apoptotic cells, demonstrating the important contribution of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, CED-1s adaptor CED-6, and the large GTPase dynamin (DYN-1) promote the recruitment of autophagosomes to phagosomes. Moreover, the subsequent fusion of autophagosomes with phagosomes requires the functions of the small GTPase RAB-7 and the HOPS complex. Our findings reveal that, unlike the single-membrane, LC3- associated phagocytosis (LAP) vesicles reported for mammalian phagocytes, canonical autophagosomes function in the clearance of C. elegans apoptotic cells. These findings add autophagosomes to the collection of intracellular organelles that contribute to phagosome maturation, identify novel crosstalk between the autophagy and phagosome maturation pathways, and discover the upstream factors that initiate this crosstalk.

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Small differences make a big impact: Structural insights into the differential function of the 2 Atg8 homologs inC. elegans

Cited by 5 publications

References 0 publications

Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations

Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations

Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells in Caenorhabditis elegans

Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells inCaenorhabditis elegans

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