{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNBR1 is a multifunctional autophagy receptor that plays a central role in the selective elimination of damaged organelles and ubiquitinated protein aggregates. It achieves this by harboring multiple functional domains—including a ubiquitin‐associated (UBA) region, an LC3‐interacting region (LIR), coiled‐coil and PB1 domains—that together allow simultaneous binding to ubiquitin and ATG8 family proteins. Through these conserved features, NBR1 is essential for mediating the autophagic degradation of peroxisomes (pexophagy) and misfolded proteins, and it cooperates with p62 in cargo aggregation and delivery."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in autophagy, NBR1 has been implicated in the dynamic remodeling of the cytoskeleton; it facilitates focal adhesion turnover during cell migration by targeting these adhesion components for autophagic degradation, thereby ensuring efficient disassembly and rapid cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, NBR1 contributes to the formation and maturation of ubiquitin condensates in cooperation with p62 and other cargo receptors such as TAX1BP1. This cooperative interaction not only enhances the sequestration of ubiquitinated substrates into aggregates but also primes them for autophagic clearance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNBR1 has also been observed in the context of neurodegeneration. It is present in ubiquitin‐positive inclusions such as Lewy bodies in α‐synucleinopathies and, albeit less frequently, in neuronal intranuclear inclusions in some polyglutamine disorders, suggesting that it may modulate aggregation dynamics when the autophagic system is compromised."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, NBR1 regulates receptor trafficking; for example, its interaction with Spred2 directs activated fibroblast growth factor receptors into the lysosomal degradation pathway, thereby attenuating growth factor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNBR1 is also involved in inflammatory signaling. In adipose tissue, interaction of its PB1 domain with MEKK3 supports the formation of a signaling complex that promotes JNK activation and proinflammatory responses, linking autophagy to metabolic and inflammatory regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDuring viral infections, NBR1 is targeted and cleaved by virus-encoded proteases, contributing to a loss of function. At the same time, it participates in the degradation of key antiviral mediators such as IRF3 by binding both its phosphorylated and unphosphorylated forms, thus fine-tuning type I interferon responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn oncological contexts, NBR1 has emerged as a factor modulating tumor biology. Its expression level influences the cellular response to rapamycin in urothelial cancer by altering autophagic flux and mitochondrial function, and mutations in NBR1 may predispose to renal cell carcinoma. Moreover, genetic variants in NBR1 have been associated with phenotypic differences in syndromes such as Brooke‐Spiegler, indicating a broader role as a phenotype-modifying gene."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the specific context of mitochondrial quality control, studies indicate that NBR1 is dispensable for PARK2-mediated mitophagy, suggesting redundancy among autophagic adaptors during the clearance of damaged mitochondria."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiophysical investigations into the folding of the NBR1 PB1 domain reveal that it undergoes a multi-step folding process with distinct transition states, insights that are important for understanding how its structural dynamics underpin adaptor function and oligomerization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vascular endothelial cells, NBR1-mediated autophagy has a protective role against arsenite-induced oxidative stress and apoptotic cell death. By promoting the degradation of caspase 8, NBR1 helps maintain endothelial integrity under toxic conditions, offering potential therapeutic avenues in cardiovascular disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLastly, alterations in cytosolic levels of NBR1 have been proposed as a biomarker for infectious conditions such as melioidosis. Elevated NBR1 levels, coinciding with autophagy deficiency and increased inflammatory cytokines, correlate with disease severity and may serve as a diagnostic indicator."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elizabeth Deosaran, Kenneth B Larsen, Rong Hua, et al. 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