Let´s try this challenge!:
Recipe to get a spanish rebellion against the Holy Roman Empire
First, to get a spanish rebellion against the Holy Roman Empire (and not a rebellion against the spanish king who is also the Holy Roman Emperor as was the case with the Revolt of the Comuneros) you need for the Spanish kingdoms to be part of the HRE. The "Universal Monarchy" of Emperor Charles von Habsburg was a massive personal union of multiple kingdoms, duchies and counties that only had in common the fact that they had the same ruler, and that ruler was elected as Holy Roman Emperor. Also, this direct connection with the HRE ended with Charles´ abdication, when the Habsburgs Domains where divided between the Austrian and Spanish branches of the family. Here, we arrive to my first POD: The childless death of Ferdinand, brother of Emperor Charles, before the abdication. OTL, Ferdinand became Holy Roman Emperor after Charles retired and founded the "Austrian" branch of the family, getting the Empire, Austria, Bohemia and Hungary in the division of the Habsburgs Domains. He was the prinicipal obstacle against Charles´ dream to maintain all of his domains united with his son Phillip (OTL Phillip II, King of Spain) as his only heir. Without him, Charles can leave all of his titles to Phillip, so the King of Spain and the Emperor of the HRE can remain being the same person (if the fear of the Super-Habsburg Empire being permanent doesnt make the different princes change their ideas and elect a weaker emperor, or accept the bribes made by the French to select their king as emperor.).
Second, you need to get the "Casa de Austria" to still be seen as a foreign rulers who dont care about the spanish kingdoms, or at least, to not care about Castile. While Charles always had a foreign air, Phillip II and his sucessors were spaniards, and considered themselves as such. In fact, it was said that Phillip was too much spanish for the german princes of the Empire to like him (and elect him). If Charles decided to select one place as permanent capital of his domains, and that place was out of Spain, or if Phillip II were to be born and raised out of Spain (lets say, the Netherlands) you could get a second POD capable of doing just that.
Third, increase the amount of taxes, wars and centralization policies made by Charles and his heirs. If you want a revolt in Spain during the 16th and 17th centuries (and 18th and 19th centuries too) the only thing that the King needs to do is to increase taxes and military contributions of all constituent parts of the "Universal Monarchy" to pay for eternal wars that only benefit one part of it (example: Aragonese and Portuguese fighting wars that only benefit Castile, or Aragonese fighting in the Netherlands in a war that doesnt benefit Aragon´s interests at all, or Castile paying the lion´s share of such wars because nobody else wants to pay) , and trample their individual laws, rights, traditions and fueros in the process, acting like there was only one kingdom and not a personal union of different kingdoms. Trying to centralize the Habsburgs Domains/HRE and fight the Wars of Religion will do nicely to generate the conditions for a revolt.
Fourth, to guarantee the success of the revolt, match it with other revolts, wars or even get a foreign intervention at the same time. If the Empire is too occupied with the Protestants, the Dutch, the Turks, the French, the English and/or the Portuguese, it cant stop the spanish.
The next steps are optional to get a succesful rebellion, but it will help.
Fifth, get the survival of the Avis Dynasty in Portugal as another POD. With this, you get "a not that foreign" dynasty with a claim to the Spanish kingdoms for any revolt with the intention of bringing down the House of Austria. Also, you get a reason for a Portuguese intervention in the revolts. Without the Avis, the only other dynasties with a claim strong enough to compete with the Habsburgs for the Spanish Thrones are the french ones, and there isnt a local spanish family strong enough to unite everybody behind them.
Sixth, involve the Reform and Counterreform Conflict somehow, if protestantism gets support in Spain or in the Habsburg court, that can generate enough friction for a long and strong revolt. (For the Know How, just ask OTL Netherlands.)
Note: The incorporation de iure of the Spanish kingdoms to the HRE can be part of those impopular centralization measures that will contribute to the start of the Revolt. It must be remembered that while the Habsburgs where Kings of Hungary and Holy Roman Emperors until the HRE´s dissolution, they never incorporated Hungary to the Empire. So incorporating the Spanish Kingdoms to the Empire is a divergence so big that can be included as its own POD.