Ndfip2 in TrkA-expressing sensory neurons regulates noxious mechanosensation through control of TrkA signaling and protein levels.

Nociception, the neural process underlying pain detection, is modulated by the NGF/TrkA signaling axis. Although anti-NGF antibodies can alleviate chronic pain, their clinical application is limited by adverse effects, underscoring the need to identify downstream regulators of this pathway. One such mechanism involves TrkA ubiquitination mediated by Nedd4 E3 ubiquitin ligases, whose activity is modulated by Nedd4 family interacting protein 2 (Ndfip2). Notably, Ndfip2 expression is regulated by TrkA signaling under pain conditions. Here, we characterize the physiological and molecular roles of Ndfip2 in sensory neurons. We demonstrate that Ndfip2 localizes to the endoplasmic reticulum and Golgi apparatus and interacts with TrkA in sensory neurons. Conditional deletion of Ndfip2 in TrkA-expressing cells selectively alters mechanical nociception. Mechanistically, loss of Ndfip2 decreases total TrkA protein levels, downstream activation, and cell-surface exposition, particularly in male-derived dorsal root ganglia neurons. Conversely, Ndfip2 expression reduces mature glycosylated TrkA and promotes the accumulation of non-glycosylated forms, consistent with impaired receptor maturation. Together, these findings identify Ndfip2 as a post-translational regulator of TrkA in TrkA-lineage sensory neurons and establish its in vivo role in mechanical nociception.