Abstract
Nucleic acid - protein interactions are critical for regulating gene activation in the nucleus. In the cytoplasm, however, potential nucleic acid-protein functional interactions are less clear. The emergence of a large and expanding number of non-coding RNAs and DNA fragments raises the possibility that the cytoplasmic nucleic acids may interact with cytoplasmic cellular components to directly alter key biological processes within the cell. We now show that both natural and synthetic nucleic acids, collectively XNAs, when introduced to the cytoplasm of live cell cardiac myocytes, markedly enhance contractile function via a mechanism that is independent of new translation, activation of the TLR-9 pathway or by altered intracellular Ca 2+ cycling. Findings show a steep XNA oligo length-dependence, but not sequence dependence or nucleic acid moiety dependence, for cytoplasmic XNAs to hasten myocyte relaxation. XNAs localized to the sarcomere in a striated pattern and bound the cardiac troponin regulatory complex with high affinity in an electrostatic-dependent manner. Mechanistically, XNAs phenocopy PKA-based modified troponin to cause faster relaxation. Collectively, these data support a new role for cytoplasmic nucleic acids in directly modulating live cell cardiac performance and raise the possibility that cytoplasmic nucleic acid - protein interactions may alter functionally relevant pathways in other cell types.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-9 |
| Number of pages | 9 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 130 |
| DOIs | |
| State | Published - May 1 2019 |
Fingerprint
Keywords
- Contraction
- DNA
- RNA
- Sarcomere
- Troponin
PubMed: MeSH publication types
- Journal Article
Cite this
Cytoplasmic nucleic acid-based XNAs directly enhance live cardiac cell function by a Ca 2+ cycling-independent mechanism via the sarcomere . / Thompson, Brian R; Soller, Kailey J.; Vetter, Anthony; Yang, Jing; Veglia, Gianluigi; Bowser, Michael; Metzger, Joseph M.
In: Journal of Molecular and Cellular Cardiology, Vol. 130, 01.05.2019, p. 1-9.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cytoplasmic nucleic acid-based XNAs directly enhance live cardiac cell function by a Ca 2+ cycling-independent mechanism via the sarcomere
AU - Thompson, Brian R
AU - Soller, Kailey J.
AU - Vetter, Anthony
AU - Yang, Jing
AU - Veglia, Gianluigi
AU - Bowser, Michael
AU - Metzger, Joseph M
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Nucleic acid - protein interactions are critical for regulating gene activation in the nucleus. In the cytoplasm, however, potential nucleic acid-protein functional interactions are less clear. The emergence of a large and expanding number of non-coding RNAs and DNA fragments raises the possibility that the cytoplasmic nucleic acids may interact with cytoplasmic cellular components to directly alter key biological processes within the cell. We now show that both natural and synthetic nucleic acids, collectively XNAs, when introduced to the cytoplasm of live cell cardiac myocytes, markedly enhance contractile function via a mechanism that is independent of new translation, activation of the TLR-9 pathway or by altered intracellular Ca 2+ cycling. Findings show a steep XNA oligo length-dependence, but not sequence dependence or nucleic acid moiety dependence, for cytoplasmic XNAs to hasten myocyte relaxation. XNAs localized to the sarcomere in a striated pattern and bound the cardiac troponin regulatory complex with high affinity in an electrostatic-dependent manner. Mechanistically, XNAs phenocopy PKA-based modified troponin to cause faster relaxation. Collectively, these data support a new role for cytoplasmic nucleic acids in directly modulating live cell cardiac performance and raise the possibility that cytoplasmic nucleic acid - protein interactions may alter functionally relevant pathways in other cell types.
AB - Nucleic acid - protein interactions are critical for regulating gene activation in the nucleus. In the cytoplasm, however, potential nucleic acid-protein functional interactions are less clear. The emergence of a large and expanding number of non-coding RNAs and DNA fragments raises the possibility that the cytoplasmic nucleic acids may interact with cytoplasmic cellular components to directly alter key biological processes within the cell. We now show that both natural and synthetic nucleic acids, collectively XNAs, when introduced to the cytoplasm of live cell cardiac myocytes, markedly enhance contractile function via a mechanism that is independent of new translation, activation of the TLR-9 pathway or by altered intracellular Ca 2+ cycling. Findings show a steep XNA oligo length-dependence, but not sequence dependence or nucleic acid moiety dependence, for cytoplasmic XNAs to hasten myocyte relaxation. XNAs localized to the sarcomere in a striated pattern and bound the cardiac troponin regulatory complex with high affinity in an electrostatic-dependent manner. Mechanistically, XNAs phenocopy PKA-based modified troponin to cause faster relaxation. Collectively, these data support a new role for cytoplasmic nucleic acids in directly modulating live cell cardiac performance and raise the possibility that cytoplasmic nucleic acid - protein interactions may alter functionally relevant pathways in other cell types.
KW - Contraction
KW - DNA
KW - RNA
KW - Sarcomere
KW - Troponin
UR - http://www.scopus.com/inward/record.url?scp=85063108955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063108955&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2019.02.016
DO - 10.1016/j.yjmcc.2019.02.016
M3 - Article
C2 - 30849419
AN - SCOPUS:85063108955
VL - 130
SP - 1
EP - 9
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -