Bidirectional Human-Swine Transmission of Seasonal Influenza A(H1N1)pdm09 Virus in Pig Herd, France, 2018.

In 2018, a veterinarian became sick shortly after swabbing sows exhibiting respiratory syndrome on a farm in France. Epidemiologic data and genetic analyses revealed consecutive human-to-swine and swine-to-human influenza A(H1N1)pdm09 virus transmission, which occurred despite some biosecurity measures. Providing pig industry workers the annual influenza vaccine might reduce transmission risk.

Kv7.1 (KCNQ1) properties and channelopathies.

KCNQ1 is the pore-forming subunit of a channel complex whose expression and function have been rather well characterized in the heart. Almost 300 mutations of KCNQ1 have been identified in patients and a vast majority of the described mutations are linked to the long QT syndrome. Only a few mutations are linked to other pathologies such as atrial fibrillation and the short QT syndrome. However, a considerable amount of work remains to be done to get a clear picture of the molecular mechanisms responsible for the pathogenesis related to each mutation. The present review gives three examples of recent studies towards this goal and illustrates the diversity of the molecular mechanisms involved.

14-3-3 is a regulator of the cardiac voltage-gated sodium channel Nav1.5.

The voltage-sensitive Na(+) channel Na(v)1.5 plays a crucial role in generating and propagating the cardiac action potential and its dysfunction promotes cardiac arrhythmias. The channel takes part into a large molecular complex containing regulatory proteins. Thus, factors that modulate its biosynthesis, localization, activity, and/or degradation are of great interest from both a physiological and pathological standpoint. Using a yeast 2-hybrid screen, we unveiled a novel partner, 14-3-3eta, interacting with the Na(v)1.5 cytoplasmic I interdomain. The interaction was confirmed by coimmunoprecipitation of 14-3-3 and full-length Na(v)1.5 both in COS-7 cells expressing recombinant Na(v)1.5 and in mouse cardiac myocytes. Using immunocytochemistry, we also found that 14-3-3 and Na(v)1.5 colocalized at the intercalated discs. We tested the functional link between Na(v)1.5 and 14-3-3eta using the whole-cell patch-clamp configuration. Coexpressing Na(v)1.5, the beta1 subunit and 14-3-3eta induced a negative shift in the inactivation curve of the Na(+) current, a delayed recovery from inactivation, but no changes in the activation curve or in the current density. The negative shift was reversed, and the recovery from inactivation was normalized by overexpressing the Na(v)1.5 cytoplasmic I interdomain interacting with 14-3-3eta. Reversal was also obtained with the dominant negative R56,60A 14-3-3eta mutant, suggesting that dimerization of 14-3-3 is needed for current regulation. Computer simulations suggest that the absence of 14-3-3 could exert proarrhythmic effects on cardiac electrical restitution properties. Based on these findings, we propose that the 14-3-3 protein is a novel component of the cardiac Na(+) channel acting as a cofactor for the regulation of the cardiac Na(+) current.

LQT1-associated mutations increase KCNQ1 proteasomal degradation independently of Derlin-1.

Mutations in the potassium channel KCNQ1 that determine retention of the mutated proteins in the endoplasmic reticulum (ER) are associated with the autosomal dominant negative Romano-Ward LQT1 cardiac syndrome. In the present study, we have analyzed the consequences and the potential molecular mechanisms involved in the ER retention of three Romano-Ward mutations located in KCNQ1 N terminus (Y111C, L114P, and P117L). We showed that the mutant KCNQ1 proteins exhibited reduced expression levels with respect to wild-type (WT)-KCNQ1. Radiolabeling pulse-chase experiments revealed that the lower expression levels did not result from reduced rate of synthesis. Instead, using a combination of Western blot and pulse-chase experiments, we showed that the mutant channel Y111C-KCNQ1, used as a model, was ubiquitinated and degraded in the proteasome more rapidly (t((1/2)) = 82 min) than WT-KCNQ1 channel (t((1/2)) = 113 min). On the other hand, KCNQ1 degradation did not appear to involve the GTP-dependent pathway. We also showed that KCNE1 stabilized both wild-type and Y111C proteins. To identify potential actors involved in KCNQ1 degradation, we studied the implication of the ER-resident protein Derlin-1 in KCNQ1 degradation. We showed that although KCNQ1 and Derlin-1 share the same molecular complex and co-immunoprecipitate when co-expressed in HEK293FT cells, Derlin-1 did not affect KCNQ1 steady state expression and degradation. These data were confirmed in T84 cells that express endogenous KCNQ1 and Derlin-1. Small interfering RNA knock-down of Derlin-1 did not modify KCNQ1 expression level, and no interaction between endogenous KCNQ1 and Derlin-1 could be detected.