PEX14 acts as the interface linking optineurin to cell type-selective pexophagy

Li, H.; Chen, S.; Claes, Z.; Lismont, C.; Vandewinkel, B.; Hussein, M. A. F.; Costa, C. F.; Imberechts, D.; Liu, Y.; Vandenberghe, W.; Verhelst, S.; Baes, M.; Fransen, M.

doi:10.1101/2024.05.31.596776

bioRxiv · 10.1101/2024.05.31.596776

PEX14 acts as the interface linking optineurin to cell type-selective pexophagy

Li, H.·Chen, S.·Claes, Z.·Lismont, C.·Vandewinkel, B.·Hussein, M. A. F.·Costa, C. F.·Imberechts, D.·Liu, Y.·Vandenberghe, W.·Verhelst, S.·Baes, M.·Fransen, M.

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Abstract

Pexophagy, the selective degradation of peroxisomes, is essential for removing excess or dysfunctional peroxisomes, and its dysregulation is linked to various diseases. Previous research has shown that optineurin (OPTN), an autophagy receptor involved in mitophagy, aggrephagy, and xenophagy, can induce pexophagy in HEK-293 cells. However, the underlying mechanism remains unclear. In this study, we used proximity labeling to identify PEX14, a peroxisomal membrane protein, as a neighboring partner of OPTN. Biochemical analyses revealed that PEX14 and OPTN interact through their respective coiled-coil and ubiquitin-binding domains. Further analyses demonstrated that the C-terminal half of overexpressed OPTN triggers pexophagy, likely by forming oligomers with endogenous OPTN. The co-localization of PEX14-OPTN complexes with LC3, combined with the suppression of OPTN-mediated peroxisome degradation by bafilomycin A1, supports a model in which PEX14 acts as a docking site for OPTN on the peroxisomal membrane, enabling the recruitment of the autophagic machinery for OPTN-mediated pexophagy. SummaryThis study uncovers and defines the peroxisomal membrane protein PEX14 as a key player in optineurin-driven pexophagy, advancing our mechanistic understanding of this cellular process. These findings open new avenues for developing therapeutic strategies targeting diseases associated with defective pexophagy.

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Li, H., Chen, S., Claes, Z., Lismont, C., Vandewinkel, B., Hussein, M. A. F., Costa, C. F., Imberechts, D., Liu, Y., Vandenberghe, W., Verhelst, S., Baes, M., Fransen, M.. 2024-05-31. PEX14 acts as the interface linking optineurin to cell type-selective pexophagy. https://doi.org/10.1101/2024.05.31.596776

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