Molecular determinants of selective clearance of protein inclusions by autophagy

Abstract

Protein quality control is essential for cellular survival. Failure to eliminate pathogenic proteins leads to their intracellular accumulation in the form of protein aggregates. Autophagy can recognize protein aggregates and degrade them in lysosomes. However, some aggregates escape the autophagic surveillance. Here we analyse the autophagic degradation of different types of aggregates of synphilin-1, a protein often found in pathogenic protein inclusions. We show that small synphilin-1 aggregates and large aggresomes are differentially targeted by constitutive and inducible autophagy. Furthermore, we identify a region in synphilin-1, necessary for its own basal and inducible aggrephagy and sufficient for the degradation of other pro-aggregating proteins. Although the presence of this peptide is sufficient for basal aggrephagy, inducible aggrephagy requires its ubiquitination, which diminishes protein mobility on the surface of the aggregate and favours the recruitment and assembly of the protein complexes required for autophagosome formation. Our study reveals different mechanisms for cells to cope with aggregate proteins via autophagy and supports the idea that autophagic susceptibility of prone-to-aggregate proteins may not depend on the nature of the aggregating proteins per se, but on their dynamic properties in the aggregate.

Chaperone-mediated autophagy: roles in disease and aging

“…Synergy between macroautophagy and CMA is also crucial in PD and in certain tauopathies where the blockage of CMA is often compensated by activation of macroautophagy [53,[81][82][83]. This upregulation of macroautophagy is crucial for removing the toxic α-synuclein and tau oligomers to alleviate these conditions [81][82][83].…”

“…This upregulation of macroautophagy is crucial for removing the toxic α-synuclein and tau oligomers to alleviate these conditions [81][82][83].…”

“…For example, adding to the already wellcharacterized role of ubiquitin in proteasome-mediated degradation, cells utilize specific ubiquitin topology to promote aggregation of pathogenic proteins in transitory aggresomal structure for removal by macroautophagy [84]. The recent identification of enhancers that promote this type of aggrephagy of pathogenic proteins and of determinants that differentiate their degradation by basal or inducible macroautophagy [82], may allow, in the future, to upregulate specific stress-coping mechanisms to prevent overloading and subsequent blockage of other components of the proteostasis system.…”

Intracellular Salmonella induces aggrephagy of host endomembranes in persistent infections

“…54 This study analyzed clearance of SNCAIP/synphilin-1 aggregates, often found as pathogenic protein inclusions. 54 Such observation led us to examine the dynamic properties of the LGP C aggregate induced by S. Typhimurium by fluorescence recovery after photobleaching (FRAP) analysis. FRAP of late LGP C aggregates (8 hpi) showed »10% fluorescence recovery, consistent with a highly static and insoluble structure ( Fig.…”

Caspase involvement in autophagy

“…The residual materials are then recycled back to the cytosol for effective use by the cell [20]. In this manner an assortment of intracellular residents including protein aggregates [21], [22], damaged organelles [23], [24], and invading pathogens [25]- [27], as well as caspases [28], [29] can be effectively cleared from the cytosolic environment. Therefore, autophagy is primarily regarded as a pro-survival mechanism and is triggered in response to a wide array of lifethreating stimuli.…”