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Aggregation of mutant toxic proteins is a hallmark of many neuronal degenerative disorders. Cells employ various quality control measures to get rid of the proteinaceous aggresomes. Our studies find that a small UBA domain containing protein, Huntingtin Interacting Protein K (HYPK), can act as a global sensor of different toxic protein aggregates to modulate their removal by autophagy. Seed nucleation type oligomerization of HYPK forms unique structures called ‘H-granule’ that forms the scaffolding structures to sequester the poly-neddylated proteins, such as Huntingtin-exon1 aggregates. While the UBA domain of HYPK interacts with the Nedd8 moieties, an evolutionarily conserved tyrosine-type LC3 interacting region (LIR) in the N-terminal disordered nanostructure mediates the interaction with LC3. Biphasic interactions of HYPK with Nedd8 and LC3 allow it to act as bridging molecule during the formation of pre-initiation complex of autophagosome. Since HYPK’s function in autophagy is dependent upon the poly-neddylation of proteins, we deciphered the mechanism in which poly-neddylation of Huntingtin-exon1 marks its aggregates for autophagic degradation. Poly-neddylation at the lysine-15 (K-15) residue in Huntingtin-exon1 leads to the delivery of aggregates to autophagic vacuole. Huntingtin-exon1 can be subjected to different kinds of poly-neddylation in terms of Nedd8 linkages, namely Nedd8-lysine 27 (Nedd8-K27), Nedd8-lysine 48 (Nedd8-K48) and Nedd8-lysine 60 (Nedd8-K60) linkages. The Nedd8-K60 linkage of proteins causes the clearance by autophagy. Over expression of Nedd8 significantly increases the basal level of cellular autophagy that is represented by increase in Beclin-1/ATG5/ATG12 expression and conversion of LC3 from state-I to state-II. Huntingtin-exon1 can also be poly-neddylated at two other lysine residues: lysine-6 (K-6) and lysine-9 (K-9) by Nedd8-K48 and Nedd8-K27 type linkages. These two poly-neddylation phenomenon are not associated with autophagy pathway, but they are presumed to have functional roles in proteasomal degradation or secretion. Conclusively, our study finds a molecular signal that links neddylated protein aggregates and their delivery to autophagic machinery. |