Autophagy is the cellular process responsible for degrading various cellular components and damaged organelles within the lysosome. This process has emerged as central for many lymphocyte functions, ranging from homeostasis to the generation of a productive immune response. In addition to the core machinery, other molecules participate in the fine modulation of the autophagic pathway and their identification contributes to fill the gaps in our fragmented understanding of the molecular mechanisms of autophagy. Here we investigated the role of the Src homologous and collagen (SHC) family adaptor p66 and the ciliary protein intraflagellar transport 20 (IFT20) in lymphocyte autophagy. First, we show that the pro-oxidant activity of p66SHC impacts on mitochondrial integrity leading to impaired ATP production, which results in enhanced autophagic flux in B cells through the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Moreover, a reactive oxygen species (ROS)-dependent dissipation of the mitochondrial transmembrane potential triggers the degradation of mitochondria through mitophagy, which relies on the ability of p66SHC to locally recruit LC3-II and AMPK. Second, we demonstrate that IFT20 is required for lysosomal function and autophagic clearance by controlling the targeting of acid hydrolases to the lysosome in T cells. This is achieved by the recruitment of the microtubule motor dynein to the cation-independent mannose-phosphate-receptor (CI-MPR) that undergoes retrograde transport to the trans-Golgi network (TGN). Collectively, our findings provide the first evidence of mitochondrial p66SHC and a component of the IFT system as novel regulators of autophagy in B and T cells, respectively.
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|Titolo:||New insights into the basal autophagic machinery: the adaptor p66SHC and the ciliogenesis protein IFT20 are novel regulators of lymphocyte autophagy|
|Citazione:||Cassioli, C. (2019). New insights into the basal autophagic machinery: the adaptor p66SHC and the ciliogenesis protein IFT20 are novel regulators of lymphocyte autophagy.|
|Appare nelle tipologie:||8.1 Tesi Dottorato|