The Role of Helicobacter pylori CagA Protein in Inhibiting Amyloid Protein Aggregation.

Amyloids are β-sheet-rich protein aggregates with various implications in biology. Beyond their functional contributions, such as biofilm formation, amyloids are best known for their involvement in a number of human pathologies, including Alzheimer's Disease, Parkinson's Disease, and Type-two Diabetes (T2D), where they accumulate as toxic aggregates. Mounting lines of research investigations aimed at inhibiting amyloids encompass various strategies targeting different stages of amyloid formation and toxicity. Recent studies have unveiled a previously unrecognized function of the Helicobacter pylori virulence protein CagA as a potent inhibitor of amyloid formation. Herein, we highlight these findings, summarizing the current evidence suggesting that the N-terminal region of CagA interferes with multiple stages of fibril formation across a wide range of substrates, including bacterial amyloids and human disease-associated proteins. Further, depending on the protein, CagA appears to block primary nucleation, elongation, or secondary nucleation, and its activity has been mapped in part to Domain II. Together, these findings suggest that CagA functions beyond its canonical role in host signaling as a versatile regulator of protein aggregation. By highlighting this promising finding, we briefly discuss the broader implications in the context of host microbe interactions, the potential for microbial proteins to influence key molecular processes in mediating neurodegeneration, and the therapeutic potential of bacterial factors as amyloid inhibitors.