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bioRxiv · 10.1101/2021.10.20.465144

Lysosomes dock to omegasomes and ER-connected Phagophores During DNAJB12 and GABARAP-Dependent Selective-Autophagy of Misfolded P23H-Rhodopsin

Kennedy, A. S.·Ren, H. Y.·Madden, V.·Cyr, D. M.
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Abstract

We report on how the ER-associated-autophagy pathway (ERAA) delivers P23H-rhodopsin (P23H-R) to the lysosome. P23H-R accumulates in an ERAD-resistant conformation that is stabilized by DNAJB12 and Hsp70. P23H-R, DNAJB12, and FIP200 co-localize in discrete foci that punctuate the rim of omegasome rings coated by WIPI1. P23H-R tubules thread through the wall of WIPI1 rings into their central cavity. Transfer of P23H-R from ER-connected phagophores to lysosomes requires GABARAP, and is associated with the transient docking of lysosomes to WIPI1 rings. Instances of lysosomes docking to WIPI1 foci are constitutive, and increase 250% upon P23H-R expression. After departure from WIPI1 rings, new patches of P23H-R are seen in the membranes of lysosomes. The absence of GABARAP prevents transfer of P23H-R from phagophores to lysosomes without interfering with docking. These data identify lysosome docking to omegasomes as an important step in the DNAJB12 and GABARAP-dependent autophagic disposal of dominantly toxic P23H-R.

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Kennedy, A. S., Ren, H. Y., Madden, V., Cyr, D. M.. 2021-10-20. Lysosomes dock to omegasomes and ER-connected Phagophores During DNAJB12 and GABARAP-Dependent Selective-Autophagy of Misfolded P23H-Rhodopsin. https://doi.org/10.1101/2021.10.20.465144

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