On September 28th, a breakthrough paper was published by researchers from Sun Yat-sen University and Soochow University in the prominent journal Nature Communications (impactful factor: 17.694). The research, entitled “NLRP6 Potentiates PI3K/AKT Signalling by Promoting Autophagic Degradation of p85α to Drive Tumorigenesis,” elucidates a novel therapeutic strategy against tumors by disrupting the interaction between NLRP6 and p85α to inhibit the PI3K/AKT pathway.
The robust system of innate immunity serves as the organism's initial shield against pathogens, recognizing pathogen-associated molecular patterns (PAMPs) through a series of pattern recognition receptors (PRRs). These PRRs, which include the likes of C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), Toll-like receptors (TLRs), and NOD-like receptors (NLRs), function not only to thwart infection but also to safeguard internal stability.
Zooming in on NLRs, they emerge as a specialized category of intracellular proteins capable of identifying a diverse array of ligands emanating from microbial pathogens, host cells, and environmental sources, thereby playing a pivotal role in orchestrating the innate immune response.
While a wealth of studies have delved into the role of various NLRs—such as NOD1, NOD2, and NLRP3—in activating innate immune signaling pathways, with NOD1 and NOD2 known to activate the NF-κB signaling pathway upon encountering their respective PAMPs, the direct interaction of NLRs with subunits of PI3K, influencing the PI3K/AKT signaling pathway in gliomas, remains unverified.
In the burgeoning field of protein interactions as potential therapeutic targets, the alpha-helix has established itself as a crucial recognition element, providing a promising inhibitory model for macromolecule interactions. The research brings to light the fact that NLRP6 promotes the degradation of p85α by establishing a direct interaction with it, consequently propelling tumor growth.
The study introduces a compelling anti-tumor effect by interfering with the NLRP6/p85α interaction via Pep9. It highlights that NLRP6, serving as a bridging protein that interacts with p85α, recruits RBX1 to ubiquitinate p85α through the OPTN-mediated autophagic degradation pathway, subsequently activating the PI3K/AKT signaling pathway to fuel tumor progression.
Providing a concrete foundation, the research validates that rupturing the interaction between NLRP6 and p85α to obstruct the PI3K/AKT pathway may unfurl as an effective strategy in tumor combat.
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