TY - JOUR
T1 - RetroCHMP3 blocks budding of enveloped viruses without blocking cytokinesis
AU - Rheinemann, Lara
AU - Downhour, Diane Miller
AU - Bredbenner, Kate
AU - Mercenne, Gaelle
AU - Davenport, Kristen A.
AU - Schmitt, Phuong Tieu
AU - Necessary, Christina R.
AU - McCullough, John
AU - Schmitt, Anthony P.
AU - Simon, Sanford M.
AU - Sundquist, Wesley I.
AU - Elde, Nels C.
N1 - Funding Information:
We thank Larry Williams and Brenda Webb from the Michale E. Keeling Center for Comparative Medicine and Research at the University of Texas MD Anderson Cancer Center for squirrel monkey blood samples; Benoit de Thoisy and Christophe Duplais from the Institut Pasteur de la Guyane; Annika Paukner and Angela Ruggiero for capuchin monkey blood samples from the Laboratory of Comparative Ethology, NICHD; and Utah’s Hogle Zoo for spider monkey blood samples. We thank Dustin Hancks for helpful discussion, Janet Iwasa for artwork, Linda Nikolova and David Belnap at the University of Utah Electron Microscopy Core for assistance with thin-section electron microscopy, Douglas Mackay and Katharine Ullman for helpful discussion on cytokinesis experiments, Marina Bleck for advice on live-cell imaging, and Daniel Johnson and Joan Pulupa for maintenance of the TIRF microscope at Rockefeller University. Immunofluorescence microscopy was performed at the University of Utah Cell Imaging Core. Flow cytometry was performed at the University of Utah Flow Cytometry Core. This work was supported by NIH grants R37 AI 51174 (to W.I.S.), P50 AI150464 (to N.C.E.), K01 OD030059 (to K.A.D.) and AI121880 (to A.P.S.); NIH / NIGMS grant 5R01GM119585 (to S.M.S.); USDA NIFA grant 1010021 (to A.P.S.); a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award (to N.C.E.); and a Pew Charitable Trusts Innovation Fund Award (to W.I.S. and N.C.E.).
Funding Information:
We thank Larry Williams and Brenda Webb from the Michale E. Keeling Center for Comparative Medicine and Research at the University of Texas MD Anderson Cancer Center for squirrel monkey blood samples; Benoit de Thoisy and Christophe Duplais from the Institut Pasteur de la Guyane; Annika Paukner and Angela Ruggiero for capuchin monkey blood samples from the Laboratory of Comparative Ethology, NICHD; and Utah's Hogle Zoo for spider monkey blood samples. We thank Dustin Hancks for helpful discussion, Janet Iwasa for artwork, Linda Nikolova and David Belnap at the University of Utah Electron Microscopy Core for assistance with thin-section electron microscopy, Douglas Mackay and Katharine Ullman for helpful discussion on cytokinesis experiments, Marina Bleck for advice on live-cell imaging, and Daniel Johnson and Joan Pulupa for maintenance of the TIRF microscope at Rockefeller University. Immunofluorescence microscopy was performed at the University of Utah Cell Imaging Core. Flow cytometry was performed at the University of Utah Flow Cytometry Core. This work was supported by NIH grants R37 AI 51174 (to W.I.S.), P50 AI150464 (to N.C.E.), K01 OD030059 (to K.A.D.) and AI121880 (to A.P.S.); NIH/NIGMS grant 5R01GM119585 (to S.M.S.); USDA NIFA grant 1010021 (to A.P.S.); a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award (to N.C.E.); and a Pew Charitable Trusts Innovation Fund Award (to W.I.S. and N.C.E.). Conceptualization, L.R. D.M.D. G.M. W.I.S. and N.C.E.; investigation, L.R. D.M.D. K.B. G.M. K.A.D. P.T.S. C.R.N. and J.M.; supervision, A.P.S. S.M.S. W.I.S. and N.C.E.; writing – original draft, L.R. and N.C.E.; writing – review & editing, all authors. The authors declare no competing interests.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/10/14
Y1 - 2021/10/14
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2021.09.008
DO - 10.1016/j.cell.2021.09.008
M3 - Article
C2 - 34597582
AN - SCOPUS:85117165459
SN - 0092-8674
VL - 184
SP - 5419-5431.e16
JO - Cell
JF - Cell
IS - 21
ER -