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PEX14 acts as a molecular link between optineurin and the autophagic machinery to induce pexophagy

ABSTRACT: Peroxisome degradation, known as pexophagy, is essential for eliminating surplus and dysfunctional peroxisomes, with dysregulation linked to various diseases. Previous research revealed that ectopic expression of optineurin (OPTN), a versatile autophagy adaptor involved in multiple autophagic pathways (e.g., mitophagy, aggrephagy, and xenophagy), triggers pexophagy in HEK-293 cells. However, the underlying mechanism remained elusive. Here, we demonstrate that OPTN-mediated pexophagy is a cell type-specific process. In addition, using proximity labeling, we identified PEX14, a peroxisomal membrane protein, as an OPTN-interacting partner. GFP-Trap analyses confirmed this interaction and revealed that PEX14 and OPTN interact through their respective coiled-coil and C-terminal ubiquitin-binding domains, independently of ubiquitin. Furthermore, our results indicate that the C-terminal half of OPTN-GFP induces pexophagy by oligomerization with endogenous OPTN. Overall, these findings propose PEX14 as a docking factor for OPTN at the peroxisomal membrane, facilitating the connection between peroxisomes and the autophagic membrane scaffold during OPTN-mediated pexophagy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Li Hongli

LAB HEAD: Marc Fransen

PROVIDER: PXD053489 | Pride | 2025-09-23

REPOSITORIES: Pride

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Project description:Peroxisomes are critical organelles that maintain cellular redox homeostasis. Many viruses induce oxidative stress and degrade peroxisomes, but the mechanisms and consequences remain unclear. In this study, we systematically investigate how virus-induced pexophagy regulates peroxisome homeostasis. Using Newcastle disease virus (NDV) as a model, we demonstrate that NDV infection triggers excessive ROS production, activating the phosphorylation and peroxisomal localization of Ataxia-telangiectasia mutated (ATM). Activated ATM promotes the interaction between the peroxisomal receptor PEX5 and the autophagy receptor p62, driving pexophagy. Pexophagy-mediated peroxisome degradation leads to excess active iron and ROS accumulation, contributing to NDV-induced ferroptosis. Notably, this mechanism is shared by other viruses, such as vesicular stomatitis virus (VSV) and H9N2 avian influenza virus (IAV). Our study provides new insights into how virus-induced pexophagy disrupts redox homeostasis to promote ferroptosis, highlighting a novel link between viral infection, peroxisome degradation, and programmed cell death.

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Control of protein accumulation by the LON2 peroxisomal protease and autophagy

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Project description:Crucial metabolic functions of peroxisomes rely on a variety of peroxisomal membrane proteins (PMPs). While mRNA transcripts of PMPs were shown to be colocalized with peroxisomes, the process by which PMPs efficiently couple translation with targeting to the peroxisomal membrane remained elusive. Here, we combine quantitative electron microscopy with proximity-specific ribosome profiling and reveal that translation of specific PMPs occurs on the surface of peroxisomes in the yeast Saccharomyces cerevisiae. This places peroxisomes alongside chloroplasts, mitochondria, and the endoplasmic reticulum as organelles that use localized translation for ensuring correct insertion of hydrophobic proteins into their membranes. Moreover, the correct targeting of these transcripts to peroxisomes is crucial for peroxisomal and cellular function, emphasizing the importance of localized translation for cellular physiology.

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Phosphorylation of the receptor protein Pex5p modulates import of PTS1 cargoes into peroxisomesPhosphorylation of the receptor protein Pex5p modulates import of PTS1 cargoes into peroxisomes

Project description:Peroxisomes are dynamic organelles with vital functions in cellular metabolism and dysfunction of peroxisomes is associated with human diseases. To fulfill their multiple roles, peroxisomes rely on import of nuclear-encoded matrix proteins, most carrying a peroxisomal targeting signal (PTS) 1. The receptor Pex5p recruits PTS1-proteins for import into peroxisomes; whether and how this process is posttranslationally regulated is unknown. Here, we identify 22 phosphorylation sites of Pex5p. Yeast cells expressing phospho-mimicking Pex5p-S507/523D (Pex5p-2D) show a decreased peroxisomal import of GFP-SKL. We show that the binding affinity between PTS1-protein and Pex5p-2D is reduced. An in vivo analysis of the effect of the phosphomimicking mutants on all known PTS1-proteins revealed that import of most, but not all, cargo proteins is affected. The physiological effect of the phosphomimetic mutations correlate with the binding affinity of the corresponding extended PTS1-sequences. Thus, we report a novel Pex5p phosphorylation-dependent mechanism for regulating PTS1-protein import into peroxisomes.

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