Mechanoregulation of the RNA-binding protein hnRNPC in a failed heart

Cardiomyocyte remodeling and functional changes
occur after cardiomyocyte injury.
The researchers investigated the role of
RNA-binding protein heteroribonucleoprotein C (hnRNPC) in cardiocontractile protein regulation.
hnRNPC expression is upregulated in diseased human heart tissue and transferred from nucleus to sarcomere
of cardiomyocytes in the mouse infarct marginal zone.
This translocation is controlled by cytoskeletal tension, and hnRNPC is involved
in the local translation of sarcomeres.
Genes involved in mechanical transformation, including Jap1, show differential splicing
when hnRNPCs in heart failure patients are knocked out in vitro or intratissue.
Mechanical regulation helps clarify heart failure

Heart disease is characterized by a strong remodeling of the extracellular matrix (ECM), which eventually leads to heart failure
.
Cardiomyocytes reexpress fetal contractile proteins through transcriptional and post-transcriptional processes such as selective splicing (AS), thereby responding
to subsequent biomechanical stress.
Here, we demonstrate that heterogeneous ribonucleoprotein C (hnRNPC) is upregulated and relocated to the sarcomere Z-disc
upon pathological remodeling of ECM.
We found that this is an active site for local translation, where ribonucleoproteins bind
to translation mechanisms.
Changes in hnRNPC expression, phosphorylation, and localization can be determined mechanically and affect AS of MRNA involved in mechanical conduction and cardiovascular disease, including the Hippo pathway effector Yes-associated protein 1
.
We believe that cardiac ECM remodeling acts as a switch in RNA metabolism by influencing the relevant regulatory proteins of the spliceosome device
.
These findings provide new insights
into the mechanism of mRNA homeostasis mechanical regulation under pathological conditions.