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1.
EMBO J ; 38(22): e101994, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31625181

RESUMEN

Mammalian homologs of yeast Atg8 protein (mAtg8s) are important in autophagy, but their exact mode of action remains ill-defined. Syntaxin 17 (Stx17), a SNARE with major roles in autophagy, was recently shown to bind mAtg8s. Here, we identified LC3-interacting regions (LIRs) in several SNAREs that broaden the landscape of the mAtg8-SNARE interactions. We found that Syntaxin 16 (Stx16) and its cognate SNARE partners all have LIR motifs and bind mAtg8s. Knockout of Stx16 caused defects in lysosome biogenesis, whereas a Stx16 and Stx17 double knockout completely blocked autophagic flux and decreased mitophagy, pexophagy, xenophagy, and ribophagy. Mechanistic analyses revealed that mAtg8s and Stx16 control several properties of lysosomal compartments including their function as platforms for active mTOR. These findings reveal a broad direct interaction of mAtg8s with SNAREs with impact on membrane remodeling in eukaryotic cells and expand the roles of mAtg8s to lysosome biogenesis.


Asunto(s)
Autofagosomas/metabolismo , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Autofagia , Lisosomas/metabolismo , Proteínas Qa-SNARE/metabolismo , Sintaxina 16/metabolismo , Secuencias de Aminoácidos , Familia de las Proteínas 8 Relacionadas con la Autofagia/genética , Células HEK293 , Células HeLa , Humanos , Redes y Vías Metabólicas , Unión Proteica , Dominios Proteicos , Proteínas Qa-SNARE/antagonistas & inhibidores , Proteínas Qa-SNARE/genética , ARN Interferente Pequeño/genética , Sintaxina 16/antagonistas & inhibidores , Sintaxina 16/genética
2.
J Mol Biol ; 433(13): 166987, 2021 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-33845085

RESUMEN

Autophagy is a highly conserved degradative pathway, essential for cellular homeostasis and implicated in diseases including cancer and neurodegeneration. Autophagy-related 8 (ATG8) proteins play a central role in autophagosome formation and selective delivery of cytoplasmic cargo to lysosomes by recruiting autophagy adaptors and receptors. The LC3-interacting region (LIR) docking site (LDS) of ATG8 proteins binds to LIR motifs present in autophagy adaptors and receptors. LIR-ATG8 interactions can be highly selective for specific mammalian ATG8 family members (LC3A-C, GABARAP, and GABARAPL1-2) and how this specificity is generated and regulated is incompletely understood. We have identified a LIR motif in the Golgi protein SCOC (short coiled-coil protein) exhibiting strong binding to GABARAP, GABARAPL1, LC3A and LC3C. The residues within and surrounding the core LIR motif of the SCOC LIR domain were phosphorylated by autophagy-related kinases (ULK1-3, TBK1) increasing specifically LC3 family binding. More distant flanking residues also contributed to ATG8 binding. Loss of these residues was compensated by phosphorylation of serine residues immediately adjacent to the core LIR motif, indicating that the interactions of the flanking LIR regions with the LDS are important and highly dynamic. Our comprehensive structural, biophysical and biochemical analyses support and provide novel mechanistic insights into how phosphorylation of LIR domain residues regulates the affinity and binding specificity of ATG8 proteins towards autophagy adaptors and receptors.


Asunto(s)
Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Células HEK293 , Células HeLa , Humanos , Mamíferos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Fosforilación , Unión Proteica , Dominios Proteicos , Proteínas Serina-Treonina Quinasas/metabolismo
3.
Dev Cell ; 49(4): 509-525.e12, 2019 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-30982665

RESUMEN

The clearance of damaged or dysfunctional mitochondria by selective autophagy (mitophagy) is important for cellular homeostasis and prevention of disease. Our understanding of the mitochondrial signals that trigger their recognition and targeting by mitophagy is limited. Here, we show that the mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) and NIPSNAP2 accumulate on the mitochondria surface upon mitochondrial depolarization. There, they recruit proteins involved in selective autophagy, including autophagy receptors and ATG8 proteins, thereby functioning as an "eat me" signal for mitophagy. NIPSNAP1 and NIPSNAP2 have a redundant function in mitophagy and are predominantly expressed in different tissues. Zebrafish lacking a functional Nipsnap1 display reduced mitophagy in the brain and parkinsonian phenotypes, including loss of tyrosine hydroxylase (Th1)-positive dopaminergic (DA) neurons, reduced motor activity, and increased oxidative stress.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Mitofagia/fisiología , Proteínas de Pez Cebra/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Autofagia/fisiología , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia , Proteínas Portadoras/metabolismo , Células HEK293 , Células HeLa , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Neuronas/metabolismo , Unión Proteica , Proteínas de Unión al ARN/metabolismo , Proteína Sequestosoma-1/metabolismo , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Pez Cebra
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