Reductive evolution in the structure of the microsporidian proteasome.

Proteasomes play an essential role in the life cycle of intracellular pathogens with extracellular stages by ensuring proteostasis in environments with limited resources. In microsporidia, divergent parasites with extraordinarily streamlined genomes, the proteasome complexity and structure are unknown, which limits our understanding of how these unique pathogens adapt and compact essential eukaryotic complexes. We present cryo-electron microscopy structures of the microsporidian 20S and 26S proteasome isolated from dormant or germinated Vairimorpha necatrix spores. The presence of distinct densities within the central cavity of the dormant spore proteasome suggests reduced activity in the environmental stage. In contrast, the absence of these densities and the existence of 26S particles post-germination indicates rapid reactivation of proteasomes after host infection. Structual and phylogenetic analyses reveal that microsporidian proteasomes have undergone extreme reductive evolution, lost three regulatory proteins, and compacted nearly every subunit. The highly derived microsporidian proteasome structure presented here reinforces the feasibility of the development of specific inhibitors and provides insight into the unique evolution and biology of these medically and economically important pathogens.