TY - JOUR
T1 - Structural divergence creates new functional features in alphavirus genomes
AU - Kutchko, Katrina M.
AU - Madden, Emily A.
AU - Morrison, Clayton
AU - Plante, Kenneth S.
AU - Sanders, Wes
AU - Vincent, Heather A.
AU - Cisneros, Marta C.Cruz
AU - Long, Kristin M.
AU - Moorman, Nathaniel J.
AU - Heise, Mark T.
AU - Laederach, Alain
N1 - Funding Information:
National Institutes of Health [HL111527 to A.L., GM101237 to A.L., HG008133 to A.L., AI03311 to N.J.M., AI123811 to N.J.M., AI109680 to M.T.H., AI109761 to M.T.H., AI107810 to M.T.H., AI137887 to M.T.H., A.L. and N.J.M., AI007151-36A1 to K.S.P., AI126730 to K.S.P.]; National Science Foundation [DGE-1144081 to K.M.K.]; North Carolina University Cancer Research Fund (to N.J.M.). The open access publication charge for this paper has been waived by Oxford University Press - NA R Editorial Board members are entitled to one free paper per year in recognition of their work on behalf of the journal. Conflict of interest statement. None declared.
Funding Information:
National Institutes of Health [HL111527 to A.L., GM101237 to A.L., HG008133 to A.L., AI03311 to N.J.M., AI123811 to N.J.M., AI109680 to M.T.H., AI109761 to M.T.H., AI107810 to M.T.H., AI137887 to M.T.H., A.L. and N.J.M., AI007151-36A1 to K.S.P., AI126730 to K.S.P.]; National Science Foundation [DGE-1144081 to K.M.K.]; North Carolina University Cancer Research Fund (to N.J.M.). The open access publication charge for this paper has been waived by Oxford University Press – NAR Editorial Board members are entitled to one free paper per year in recognition of their work on behalf of the journal. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2018.
PY - 2018/4/20
Y1 - 2018/4/20
N2 - Alphaviruses are mosquito-borne pathogens that cause human diseases ranging from debilitating arthritis to lethal encephalitis. Studies with Sindbis virus (SINV), which causes fever, rash, and arthralgia in humans, and Venezuelan equine encephalitis virus (VEEV), which causes encephalitis, have identified RNA structural elements that play key roles in replication and pathogenesis. However, a complete genomic structural profile has not been established for these viruses. We used the structural probing technique SHAPE-MaP to identify structured elements within the SINV and VEEV genomes. Our SHAPE-directed structural models recapitulate known RNA structures, while also identifying novel structural elements, including a new functional element in the nsP1 region of SINV whose disruption causes a defect in infectivity. Although RNA structural elements are important for multiple aspects of alphavirus biology, we found the majority of RNA structures were not conserved between SINV and VEEV. Our data suggest that alphavirus RNA genomes are highly divergent structurally despite similar genomic architecture and sequence conservation; still, RNA structural elements are critical to the viral life cycle. These findings reframe traditional assumptions about RNA structure and evolution: rather than structures being conserved, alphaviruses frequently evolve new structures that may shape interactions with host immune systems or co-evolve with viral proteins.
AB - Alphaviruses are mosquito-borne pathogens that cause human diseases ranging from debilitating arthritis to lethal encephalitis. Studies with Sindbis virus (SINV), which causes fever, rash, and arthralgia in humans, and Venezuelan equine encephalitis virus (VEEV), which causes encephalitis, have identified RNA structural elements that play key roles in replication and pathogenesis. However, a complete genomic structural profile has not been established for these viruses. We used the structural probing technique SHAPE-MaP to identify structured elements within the SINV and VEEV genomes. Our SHAPE-directed structural models recapitulate known RNA structures, while also identifying novel structural elements, including a new functional element in the nsP1 region of SINV whose disruption causes a defect in infectivity. Although RNA structural elements are important for multiple aspects of alphavirus biology, we found the majority of RNA structures were not conserved between SINV and VEEV. Our data suggest that alphavirus RNA genomes are highly divergent structurally despite similar genomic architecture and sequence conservation; still, RNA structural elements are critical to the viral life cycle. These findings reframe traditional assumptions about RNA structure and evolution: rather than structures being conserved, alphaviruses frequently evolve new structures that may shape interactions with host immune systems or co-evolve with viral proteins.
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U2 - 10.1093/nar/gky012
DO - 10.1093/nar/gky012
M3 - Article
C2 - 29361131
AN - SCOPUS:85048711670
SN - 0305-1048
VL - 46
SP - 3657
EP - 3670
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 7
ER -