Caseinolytic Protease P: A Therapeutic Nexus in Infection, Inflammation, and Immunity.

Caseinolytic protease P (ClpP) is a highly conserved serine protease that plays a pivotal role in protein homeostasis and quality control in bacteria, mitochondria of mammalian cells, and plant chloroplasts. As the proteolytic core of the ATP-dependent Clp protease complex, ClpP partners with regulatory ATPases (e.g., ClpX, ClpA) to degrade misfolded, damaged, or regulatory proteins. In bacteria, ClpP is crucial for survival under host-imposed stresses and modulates virulence through degradation of transcriptional regulators and signaling proteins, contributing to immune evasion, dormancy, and persistence. Particularly in pathogens like Mycobacterium tuberculosis, Staphylococcus aureus, and Listeria monocytogenes, ClpP supports intracellular adaptation and resistance, making it a promising target against antimicrobial-resistant (AMR) infections. In mammalian cells, mitochondrial ClpP ensures oxidative phosphorylation efficiency and regulates innate immunity. Loss of ClpP function can result in mitochondrial dysfunction, triggering immune activation via cytosolic leakage of mitochondrial DNA and subsequent cGAS-STING pathway stimulation. ClpP also influences cytokine production and immune cell differentiation. This dual role of ClpP in pathogen virulence and host immune modulation highlights its potential as an immunotherapeutic target. Pharmacological manipulation of ClpP activity offers novel opportunities for treating infectious diseases, inflammatory conditions, and cancer. Further investigation into ClpP's regulatory mechanisms could inform next-generation host-pathogen intervention strategies.