Conversation so far:
What happened in France during Charles V's reign?
Much of Charles's reign was taken up by conflicts with France, which found itself encircled by Charles's empire while it still maintained ambitions in Italy.
Conflicts with France during Charles V's reign were over what?
Charles allied with England and Pope Leo X against the French and the Venetians, and was highly successful, driving the French out of Milan.

Question: What is the most important fact in this article?
Self-contained rewrite: What is the most important fact in this article about Charles V and the Holy Roman Empire?