Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency

Abstract

Peroxisomes share metabolic pathways with other organelles and peroxisomes are embedded into key cellular processes. However, the specific function of many peroxisomal proteins remains unclear and restricted knowledge of the peroxisomal protein interaction network limits a precise mapping of this network into the cellular metabolism. Inborn peroxisomal disorders are autosomal or X-linked recessive diseases that affect peroxisomal biogenesis (PBD) and/or peroxisomal metabolism. Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. To investigate the phenotypic complexity of PEX26 deficiency, we performed a combined organelle protein interaction screen and network medicine approach and 1) analyzed whether PEX26 establishes interactions with other peroxisomal proteins, 2) deciphered the PEX26 interaction network, 3) determined how PEX26 is involved in further processes of peroxisomal biogenesis and metabolism, and 4) showed how variant-specific disruption of protein-protein interactions (edgetic perturbations) may contribute to phenotypic variability in PEX26 deficient patients. The discovery of 14 novel protein-protein interactions for PEX26 revealed a hub position of PEX26 inside the peroxisomal interactome. Analysis of edgetic perturbations of PEX26 variants revealed a strong correlation between the number of affected protein-protein interactions and the molecular phenotype of matrix protein import. The role of PEX26 in peroxisomal biogenesis was expanded encompassing matrix protein import, division and proliferation, and membrane assembly. Moreover, the PEX26 interaction network intersects with cellular lipid metabolism at different steps. The results of this study expand the knowledge about the function of PEX26 and refine genotype-phenotype correlations, which may contribute to our understanding of the underlying disease mechanism of PEX26 deficiency.

Insights into the Structure and Function of the Pex1/Pex6 AAA-ATPase in Peroxisome Homeostasis

“…Pex15 or PEX26 is an essential partner for Pex1/Pex6; Pex15/PEX26-deficient cells cannot sustain matrix protein import and accumulate ubiquitinated Pex5 at the peroxisome membrane [103,190,192]. While Pex15 and PEX26 were originally identified as membrane anchors for Pex1/Pex6, subsequent studies, discussed below, raised the possibility that they have more active roles in recruiting Pex1/Pex6 to specific substrates and may even be substrates themselves [18,142,158,[193][194][195].…”

“…Further experimental verification is needed to characterize the interaction between PEX6 and PEX26. Both ScPex15 and HsPEX26 also share an amphipathic helix prior to the transmembrane domain that, for PEX26, has been proposed to mediate homo-oligomerization and binding to other PMPs [194,195]. As an amphipathic helix, it may also deform the peroxisome membrane.…”