Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile.
Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile.
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作者：
de Wet S;Du Toit A;Loos B
自噬通量是细胞质成分通过整个自噬途径降解的速率，通常通过监测自噬体的清除率来测量。由于自噬在人类病理学中的作用，自噬针对特定货物的具体方法最近引起了人们的广泛关注，其中特定的蛋白质货物虽然具有功能性自噬活性，但并未充分招募到自噬体区室中。在此背景下，p62/Sequestosome-1 等受体蛋白与 BRCA1 基因 1 (NBR1) 的邻居蛋白之间的动态相互作用引起了人们的关注。然而，在不同自噬活性下，受体蛋白募集和随后与自噬体一起清除的程度仍不清楚。在这里，我们采用微图案分析了雷帕霉素和亚精胺暴露对受体招募、清除和自噬体周转随时间的浓度依赖性和时间影响。我们的结果揭示了独特的自噬活性反应概况，其中自噬体和受体共定位的程度不涉及任一实体的总池，并且不以类似的方式运作。这些结果表明，自噬体周转和特定货物清除是具有固有特性的不同实体，对总功能性自噬活动有独特的贡献。这些发现对于未来的研究具有重要意义，在未来的研究中，疾病特异性蛋白质聚集体需要清除以保持细胞蛋白质稳态和活力，并强调需要辨别和更好地调整自噬机制活性和货物清除。
Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion. These results suggest that autophagosome turnover and specific cargo clearance are distinct entities with inherent properties, distinctively contributing towards total functional autophagy activity. These findings are of significance for future studies where disease specific protein aggregates require clearance to preserve cellular proteostasis and viability and highlight the need of discerning and better tuning autophagy machinery activity and cargo clearance.
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