Reverse Proteolysis Uncovers a Hidden Dimension of the Peptidome
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Proteases are classically viewed as degradative enzymes, yet they can also catalyze reverse proteolysis - a process known for decades but rarely examined in disease contexts. Here, we show that cysteine cathepsins efficiently form multi-generation cis/transpeptides, including chimeras between viral/bacterial, and human proteins, revealing a hidden layer of the peptidome complexity with direct relevance to autoimmunity. Importantly, we identified cathepsin S-generated type 1 diabetes super-agonists, directly linking reverse proteolysis to a clinically established autoantigen. Moreover, we demonstrated that this activity is pH dependent, favored by citrullination, and may represent up to 4.5% of total protease activity. To capture these products in a cellular environment, we developed a click chemistry-based technology. These findings expand the protease functional paradigm and uncover a hidden source of disease-relevant antigens.
