Lipopolysaccharide Accelerates Neuropilin-1 Protein Degradation by Activating the Large GTPase Dynamin-1 in Macrophages

Neuropilin-1 (Nrp1) is highly expressed in macrophages and plays a critical role in acute and chronic inflammation-associated diseases, such as sepsis, type II diabetes, and metabolic syndrome. Therefore, it is of importance to understand the regulation of Nrp1. It is known that lipopolysaccharide (LPS) downregulates Nrp1 mRNA levels through the NF-kappa B signaling in macrophages. However, whether and how LPS regulates Nrp1 protein degradation remain unknown. Here, we show that LPS promotes Nrp1 protein decay through a lysosome-dependent manner. Liver kinase B1 (LKB1)-Rab7 does not mediate this process. However, the large GTPase dynamin-1 (Dyn1) but not Dyn2 is involved in LPS-accelerated Nrp1 degradation. Mechanistically, LPS activates Dyn1 by attenuating p-Dyn1 (Ser774) levels, implying increased Nrp1 endocytosis and consequent degradation. As a result, blocking Nrp1 degradation by Dyn1 siRNA attenuates LPS-induced inflammatory response. Collectively, our study shows that LPS promotes Nrp1 protein degradation via a Dyn1-dependent pathway, revealing a previously uncovered role of Dyn1 in LPS-promoted Nrp1 protein decay.

Automated summary

LPS promotes Nrp1 protein degradation via a Dyn1-dependent pathway, revealing a previously unknown role of Dyn1 in LPS-regulated Nrp1 protein decay.