# Evolutionary remodeling of a remnant GET pathway factor into PEX38, an essential peroxin

## TL;DR

The paper identifies PEX38, a unique protein in parasites causing tropical diseases, which evolved from a different pathway and is crucial for parasite survival, making it a potential drug target.

## Contribution

Discovers PEX38 as a novel peroxin in trypanosomatid parasites, evolved from a remnant GET pathway and essential for glycosome biogenesis.

## Key findings

- PEX38 is an essential parasite-specific peroxin involved in glycosome protein targeting.
- PEX38 evolved from a remnant GET pathway and is unique to Euglenozoa.
- The PEX19–PEX38 interaction is a promising therapeutic target due to its essential role and absence in humans.

## Abstract

Neglected tropical diseases affect over 1.5 billion people worldwide, with trypanosomatid parasites responsible for three major diseases: African sleeping sickness, Chagas disease, and leishmaniasis. These parasites rely on glycosomes, specialized peroxisomes essential for survival, making glycosome biogenesis an Achilles’ heel for therapeutic intervention. PEX38, an essential parasite-specific peroxin absent in humans, is the first peroxin discovered outside yeast or mammals and plays a unique role in protein targeting to glycosomes, representing a promising therapeutic candidate. The research provides insights into the mechanisms of membrane protein folding and their targeting during organelle formation. These findings highlight the potential for therapeutic strategies that exploit evolutionary differences between parasites and humans.

PEX19 is a cytosolic receptor that directs membrane proteins posttranslationally to peroxisomes, as well as to mitochondria, lipid droplets, and the endoplasmic reticulum. A comprehensive Trypanosoma PEX19 interactome analysis uncovered PEX38 as an essential Euglenozoa-specific peroxin. PEX38 contains distinct domains that bind the cochaperone Hip and the PEX3-binding motif of PEX19, suggesting a role in stabilizing membrane proteins and preventing premature membrane docking. PEX38 illustrates functional repurposing in organelle biogenesis. It originated from a remnant of the GET/TRC pathway, typically responsible for the targeting of tail-anchored (TA) proteins to the endoplasmic reticulum. While most components of this machinery are absent in Euglenozoa, PEX38 has been retained and adapted to mediate peroxisomal membrane protein targeting. This evolutionary adaptation is unique to Euglenozoa. Because the PEX19–PEX38 interaction is essential for parasite viability and PEX38 has no human homologs, this complex is a promising therapeutic target against trypanosomatid parasites.