RetroCHMP3 Blocks Budding of Enveloped Viruses Without Blocking Cytokinesis

Abstract

SummaryMany 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 and therefore has limited potential to acquire adaptive mutations to counteract this co-option by viruses. Here, we describe duplicated and truncated copies of the ESCRT-III factor CHMP3 that arose independently in New World monkeys and mice and that block ESCRT-dependent virus budding. When expressed in human cells, these retroCHMP3 proteins potently inhibit the release of retroviruses, paramyxoviruses and filoviruses. RetroCHMP3 proteins have evolved to reduce interactions with other ESCRT-III factors, and to have little effect on cellular ESCRT processes, revealing routes for decoupling cellular ESCRT functions from exploitation by viruses. The repurposing of duplicated ESCRT-III proteins thus provides a mechanism to generate broad-spectrum viral budding inhibitors without disrupting highly conserved essential cellular ESCRT functions.

Recurrent Emergence of an Antiviral Defense through Repeated Retrotransposition and Truncation of CHMP3

“…Therefore, in contrast to retroCHMP3 proteins in New World monkeys, which became less cytotoxic before acquiring activating stop codons, retroCHMP3 proteins in mice had substantially less time to sample mutations, even when accounting for the shorter generation times of mice compared to primates. Consistent with the relatively early acquisition of an activating stop codon, we previously found that mouse retroCHMP3 remains significantly more cytotoxic than squirrel monkey retroCHMP3 (Rheinemann et al, 2020), raising the question of how murine retroCHMP3, with the exception of the pseudogenized copy encoded by Mus minutoides (Fig. 5A), remained intact for millions of years.…”

“…1b). These observations provide strong evidence that CHMP3 retrocopies is positively selected for antiviral activity against ESCRT-dependent enveloped viruses (Rheinemann et al, 2020). Due to the broad reliance of virus families on the ESCRT pathway, CHMP3 retrogenes could provide broad inhibitory activity against the budding of diverse virus classes.…”

“…In our sample of New World monkeys, squirrel monkeys and spider monkeys independently acquired premature stop codons that activate retroCHMP3 proteins into more potent inhibitors of virus budding (Fig. 4A and (Rheinemann et al, 2020)). To determine whether full-length retroCHMP3 proteins from other species can similarly be converted into potent virus budding inhibitors, we introduced truncating stop codons into the ORFs of retroCHMP3 encoded by woolly monkeys, owl monkeys, and pygmy marmosets.…”

“…1B, green circles). Such retrocopies encode proteins that are similar in length to the well-characterized retroCHMP3 proteins in squirrel monkeys and mice (Rheinemann et al, 2020). These retrocopies are expected to be potent inhibitors of ESCRT function due to the deletion of VPS4 binding sites and autoinhibitory sequences (Bajorek et al, 2009;Lata et al, 2008;Muziol et al, 2006;Shim et al, 2007;Stuchell-Brereton et al, 2007;Zamborlini et al, 2006), and therefore have the potential to function as virus budding inhibitors.…”

“…Next we turned to the emergence of retroCHMP3 in mice, an independently acquired variant of retroCHMP3 that can also potently inhibit virus budding (Rheinemann et al, 2020).…”