A new perspective on the autophagic and non-autophagic functions of the GABARAP protein family: a potential therapeutic target for human diseases

Chen, Jiawei; Zhao, Hong; Liu, Meiqing; Chen, Linxi

doi:10.1007/s11010-023-04800-5

Cited by 3 publications

(6 citation statements)

References 193 publications

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“…The Atg8 family is dissected into two subfamilies, LC3 and GABARAP, both needed for autophagy [26]. GABARAP subfamily members have been described as pivotal in autophagy and other cellular processes [10]. Here, we describe a new cellular platform for studying the functions of individual GABARAPs in autophagy and possibly other cellular pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Much of our present understanding of human Atg8 orthologues stems from studies on LC3B, often applying its findings to the entire family. Growing evidence indicates functional variations among the GABARAPs and LC3s subfamilies, pointing out GABARAPs unique roles in bulk and selective autophagy [10, 26, 27]. However, the high sequence and structural similarity within and across the LC3 and GABARAP subfamilies [20] requires the development of particular and sensitive readout systems for their precise and non-redundant functions.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to their roles in nonselective autophagy, GABARAPs play a critical role in several types of selective autophagy, including mitophagy, ER-phagy, Golgi-phagy, and centrosome-phagy [8, 9]. Recent studies revealed that GABARAPs also possess non-autophagic functions in immune and inflammatory responses, receptor endocytosis, vesicle trafficking, neurotransmitter transport, cilia formation, and cell adhesion [2, 10]. This suggests functional divergence among different GABARAP isoforms within autophagy and other cellular pathways [5, 11–13].…”

Section: Introductionmentioning

confidence: 99%

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A new cellular platform for studying autophagy

Goldin-Azulay,

Fraiberg,

Trofimyuk

et al. 2024

Preprint

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Atg8 proteins play a crucial role in autophagy. There is a single Atg8 isoform in yeast, while mammals have up to seven homologs categorized into LC3s and GABARAPs. The GABARAP subfamily consists of GABARAP, GABARAPL1, and GABARAPL2/GATE16, implicated in various stages along the pathway. However, the intricacies among GABARAP proteins are complex and require a more precise delineation. Here, we introduce a new cellular platform to study autophagy using CRISPR/Cas9-mediated tagging of endogenous genes of the GABARAP subfamily with different fluorescent proteins. This platform allows robust examination of autophagy by flow cytometry of cell populations and monitoring of GABARAP homologs at single-cell resolution using fluorescence microscopy. Strikingly, the simultaneous labeling of the different endogenous GABARAPs allows the identification and isolation of autophagosomes differentially marked by these proteins. Using this system, we found that the different GABARAPs are associated with different autophagosomes. We argue that this new cellular platform will be crucial in studying the unique roles of individual GABARAP proteins in autophagy and other putative cellular processes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A new cellular platform for studying autophagy

Goldin-Azulay,

Fraiberg,

Trofimyuk

et al. 2024

Preprint

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“…GABARAP, together with GABARAPL1, 2, and 3, form a family of GABA receptor-associated proteins that, with LC3 proteins, are a part of the ATG8 family, conjugation proteins that are essential for autophagy. Together with the well-established and overlapping functions between LC3 and GABARAPs in autophagophore formation, GABARAPs have a broad array of unique functions, both in autophagy and autophagy-unrelated that have been recently extensively reviewed (40)(41)(42)(43). Autophagy-related functions of GABARAPs, distinct from LC3, include autophagy initiation, cargo targeting, autophagosome-lysosomal fusion, TFEBdependent coordination of lysosomal biogenesis and capacity and selective autophagy, such as mitophagy, ERphagy, as well as autophagic degradation of Golgi and centrosomes.…”

Section: Discussionmentioning

confidence: 99%

Plasma Proteomic Signature of Mucolipidosis Type IV

Tobin,

Misko,

Miller-Browne

et al. 2024

Preprint

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Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by the loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, lysosomal abnormalities, and increased cytokine expression. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. In the current study, we analyzed 7,322 proteins in the plasma proteome and compare protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). To do so, we used aptamer-based protein profiling on plasma isolated from 18 MLIV patients and 37 aged-matched controls from a biorepository. We identified a total of 1,961 differentially expressed proteins between MLIV and control subjects, with functions spanning many major hallmarks of MLIV. Our analysis revealed a decrease in the abundance of neuronal proteins and an increase in muscle proteins, consistent with the neuronal dysfunction and muscle pathology observed in patients. In particular, lower levels of synaptic proteins (e.g., GABARAP) best correlated with disease severity. Next, we compared the plasma proteome of patients to the brain proteome from the mouse model of MLIV and identified shared alterations in 45 proteins. The up-regulated overlapping proteins were largely related to lysosomal function (e.g., ACTN2, GLB1), while the down-regulated proteins were largely related to myelination (e.g. TPPP3, CNTN2). Both signatures are consistent with our understanding of key disease hallmarks: impaired myelination and modified lysosomal function. Collectively, these data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain and suggest candidate markers relevant to MLIV pathology to be validated in future studies.

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“…Introduction Through the route of the conventional secretory pathway, FVIII is synthesized into the ER, folded and transported into the Golgi by interacting with chaperones and cargo proteins 1 . The mammalian family of ATG8 proteins, comprising GABARAP, GABARAPL1 and GABARAPL2, are currently being highly studied for their versatile roles in processes such as signaling, vesicular trafficking and autophagy 2 . We previously created CRISPR-cas9 knockouts of these genes and observed that GABARAP SKO decreased FVIII secretion (by 25%), GABARAPL1 and GABARAPL2 SKO increased FVIII secretion (by 50-100%).…”

mentioning

confidence: 99%

Insights into the differential role of GABARAPs proteins at the proteomic level

Ibrahim,

Jamil,

Oldenburg

et al. 2024

GTH Congress 2024 – 68th Annual Meeting of the Society of Thrombosis and Haemostasis Research – Building Bridges in Coagulation

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A new perspective on the autophagic and non-autophagic functions of the GABARAP protein family: a potential therapeutic target for human diseases

Cited by 3 publications

References 193 publications

A new cellular platform for studying autophagy

A new cellular platform for studying autophagy

Plasma Proteomic Signature of Mucolipidosis Type IV

Insights into the differential role of GABARAPs proteins at the proteomic level

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