Frontiers in pharmacology · 2026
Phosphatase PTP-4 downregulates ATLN-1-mediated host defense against Pseudomonas aeruginosa infection in Caenorhabditis elegans.
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Xie Jing, Shi Guojun, Wang Mo, Zhong Yuwen, Yuan Yue, Sun Lei, Ge Baoxue, Xu Ajing
Аннотация
AIM: The p38 MAPK pathway governs the core innate immune response in Caenorhabditis elegans (C. elegans), yet the negative regulatory networks preventing immune overactivation-and their potential as therapeutic targets-remain elusive. We aimed to identify novel phosphatase checkpoints in host defense, elucidate their molecular mechanisms, and validate their druggability using small-molecule interventions.
METHODS: We performed a genome-wide RNAi screen of 166 phosphatase genes in C. elegans infected with Pseudomonas aeruginosa (PA14) to identify key regulators. The molecular mechanism was dissected using yeast two-hybrid screening, Co-IP, and mutagenesis assays. Furthermore, a small-molecule screen was performed to identify compounds capable of interfering with PTP-4 function, followed by Surface Plasmon Resonance (SPR), molecular docking, and structural biology approaches to characterize compound-PTP-4 interactions.
RESULTS: PTP-4 was identified as a critical negative regulator of immunity. Genetic deficiency of ptp-4 significantly enhanced host resistance via hyperactivation of the p38 MAPK (PMK-1) pathway. Mechanistically, PTP-4 physically interacts with ATLN-1, an ER-shaping GTPase, through its phosphatase domain, thereby suppressing immune activation. Crucially, baicalin was identified through compound screening as an inhibitor of P. aeruginosa infection. Structural and biochemical analyses revealed a dual mechanism of action: baicalin directly binds to the PTP-4/ATLN-1 interface with high affinity (KD = 28.69 μM) to allosterically disrupt their complex formation, while concurrently downregulating PTP-4 protein expression. This "dual-hit" inhibition mimics the genetic loss of ptp-4, effectively unleashing the innate immune response.
CONCLUSION: Our study uncovers the PTP-4/ATLN-1 axis in the control of P. aeruginosa infection. Importantly, we provide the first proof-of-concept that this axis is a druggable target. By demonstrating that baicalin boosts host immunity through the specific dismantling of the PTP-4/ATLN-1 complex, we highlight a novel therapeutic strategy for combating bacterial infections.
METHODS: We performed a genome-wide RNAi screen of 166 phosphatase genes in C. elegans infected with Pseudomonas aeruginosa (PA14) to identify key regulators. The molecular mechanism was dissected using yeast two-hybrid screening, Co-IP, and mutagenesis assays. Furthermore, a small-molecule screen was performed to identify compounds capable of interfering with PTP-4 function, followed by Surface Plasmon Resonance (SPR), molecular docking, and structural biology approaches to characterize compound-PTP-4 interactions.
RESULTS: PTP-4 was identified as a critical negative regulator of immunity. Genetic deficiency of ptp-4 significantly enhanced host resistance via hyperactivation of the p38 MAPK (PMK-1) pathway. Mechanistically, PTP-4 physically interacts with ATLN-1, an ER-shaping GTPase, through its phosphatase domain, thereby suppressing immune activation. Crucially, baicalin was identified through compound screening as an inhibitor of P. aeruginosa infection. Structural and biochemical analyses revealed a dual mechanism of action: baicalin directly binds to the PTP-4/ATLN-1 interface with high affinity (KD = 28.69 μM) to allosterically disrupt their complex formation, while concurrently downregulating PTP-4 protein expression. This "dual-hit" inhibition mimics the genetic loss of ptp-4, effectively unleashing the innate immune response.
CONCLUSION: Our study uncovers the PTP-4/ATLN-1 axis in the control of P. aeruginosa infection. Importantly, we provide the first proof-of-concept that this axis is a druggable target. By demonstrating that baicalin boosts host immunity through the specific dismantling of the PTP-4/ATLN-1 complex, we highlight a novel therapeutic strategy for combating bacterial infections.