RetroCHMP3 blocks budding of enveloped viruses without blocking cytokinesis.

Many enveloped viruses require the endosomal sorting complexes required for transport (ESCRT) pathway to exit infected cells. This highly conserved pathway mediates essential cellular membrane fission events, which restricts the acquisition of adaptive mutations to counteract viral co-option. Here, we describe duplicated and truncated copies of the ESCRT-III factor CHMP3 that block ESCRT-dependent virus budding and arose independently in New World monkeys and mice. When expressed in human cells, these retroCHMP3 proteins potently inhibit release of retroviruses, paramyxoviruses, and filoviruses. Remarkably, retroCHMP3 proteins have evolved to reduce interactions with other ESCRT-III factors and have little effect on cellular ESCRT processes, revealing routes for decoupling cellular ESCRT functions from viral exploitation. The repurposing of duplicated ESCRT-III proteins thus provides a mechanism to generate broad-spectrum viral budding inhibitors without blocking highly conserved essential cellular ESCRT functions.

Recurrent evolution of an inhibitor of ESCRT-dependent virus budding and LINE-1 retrotransposition in primates.

Most antiviral proteins recognize specific features of viruses. In contrast, the recently described antiviral factor retroCHMP3 interferes with the "host endosomal complexes required for transport" (ESCRT) pathway to inhibit the budding of enveloped viruses. RetroCHMP3 arose independently on multiple occasions via duplication and truncation of the gene encoding the ESCRT-III factor CHMP3. However, since the ESCRT pathway is essential for cellular membrane fission reactions, ESCRT inhibition is potentially cytotoxic. This raises fundamental questions about how hosts can repurpose core cellular functions into antiviral functions without incurring a fitness cost due to excess cellular toxicity. We reveal the evolutionary process of detoxification for retroCHMP3 in New World monkeys using a combination of ancestral reconstructions, cytotoxicity, and virus release assays. A duplicated, full-length copy of retroCHMP3 in the ancestors of New World monkeys provides modest inhibition of virus budding while exhibiting subtle cytotoxicity. Ancient retroCHMP3 then accumulated mutations that reduced cytotoxicity but preserved virus inhibition before a truncating stop codon arose in the more recent ancestors of squirrel monkeys, resulting in potent inhibition. In species where full-length copies of retroCHMP3 still exist, their artificial truncation generated potent virus-budding inhibitors with little cytotoxicity, revealing the potential for future antiviral defenses in modern species. In addition, we discovered that retroCHMP3 restricts LINE-1 retrotransposition, revealing how different challenges to genome integrity might explain multiple independent origins of retroCHMP3 in different species to converge on new immune functions.

Centrosome loss in the evolution of planarians.

The centrosome, a cytoplasmic organelle formed by cylinder-shaped centrioles surrounded by a microtubule-organizing matrix, is a hallmark of animal cells. The centrosome is conserved and essential for the development of all animal species described so far. Here, we show that planarians, and possibly other flatworms, lack centrosomes. In planarians, centrioles are only assembled in terminally differentiating ciliated cells through the acentriolar pathway to trigger the assembly of cilia. We identified a large set of conserved proteins required for centriole assembly in animals and note centrosome protein families that are missing from the planarian genome. Our study uncovers the molecular architecture and evolution of the animal centrosome and emphasizes the plasticity of animal cell biology and development.