A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel

Peiqiang Feng (), Xudong Wu, Satchal K. Erramilli, Joao A. Paulo, Pawel Knejski, Steven P. Gygi, Anthony A. Kossiakoff and Tom A. Rapoport ()
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Peiqiang Feng: Harvard Medical School
Xudong Wu: Harvard Medical School
Satchal K. Erramilli: University of Chicago
Joao A. Paulo: Harvard Medical School
Pawel Knejski: University of Chicago
Steven P. Gygi: Harvard Medical School
Anthony A. Kossiakoff: University of Chicago
Tom A. Rapoport: Harvard Medical School

Nature, 2022, vol. 607, issue 7918, 374-380

Abstract: Abstract Peroxisomes are ubiquitous organelles that house various metabolic reactions and are essential for human health1–4. Luminal peroxisomal proteins are imported from the cytosol by mobile receptors, which then recycle back to the cytosol by a poorly understood process1–4. Recycling requires receptor modification by a membrane-embedded ubiquitin ligase complex comprising three RING finger domain-containing proteins (Pex2, Pex10 and Pex12)5,6. Here we report a cryo-electron microscopy structure of the ligase complex, which together with biochemical and in vivo experiments reveals its function as a retrotranslocation channel for peroxisomal import receptors. Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel. The three ring finger domains form a cytosolic tower, with ring finger 2 (RF2) positioned above the channel pore. We propose that the N terminus of a recycling receptor is inserted from the peroxisomal lumen into the pore and monoubiquitylated by RF2 to enable extraction into the cytosol. If recycling is compromised, receptors are polyubiquitylated by the concerted action of RF10 and RF12 and degraded. This polyubiquitylation pathway also maintains the homeostasis of other peroxisomal import factors. Our results clarify a crucial step during peroxisomal protein import and reveal why mutations in the ligase complex cause human disease.

Date: 2022
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DOI: 10.1038/s41586-022-04903-x

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