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Characterization of GABARAP isoforms

Þengill Fannar Jónsson, Margrét Helga Ögmundsdóttir

Autophagy is a highly conserved catabolic process present in all eukaryotic cells. In the center of the autophagy machinery are six human ATG8 genes, also known as LC3/GABARAPs. ATG8s mediate the formation of the autophagosome, and fix cargo marked for autophagic degradation to the autophagosomal membrane.
We recently discovered that GABARAP which is the highest expressed ATG8 gene has two expressed novel splicing isoforms known as GABARAP-a and GABARAP-b which are expressed across human tissues. Furthermore, these isoforms are substantially more expressed than the characterized protein isoform. These novel isoforms would lack the N-and C-terminals of whole length GABARAP respectively, thereby lacking the characterized autophagy functional domains of the protein. We generated predictions of both GABARAP-a and -b and found that GABARAP-a is likely to fold as a stable protein while GABARAP-b is not. Following our alpha fold analysis, we expressed GABARAP and GABARAP-a in different cell lines and found that both isoforms could be expressed. Interestingly we have found that GABARAP and GABARAP-a localize differently within HeLa cells with all six ATG8s knocked out. GABARAP is more prone to be spread throughout the cytoplasm and GABARAP-a localizes more at the cell membrane and in string like structures throughout the cytoplasm.
Uncovering the role of these GABARAP isoforms will be an important step for understanding the complexities of ATG8 functions in autophagy and possibly other cellular processes.


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