Fig. 7

Posttranslational modification of PD-1. As a transmembrane protein, PD-1 undergoes intricate posttranslational modifications. The primary site of focus for PD-1 is within the Golgi apparatus. Fut8 plays a pivotal role in promoting the core structure of the PD-1 protein, thereby contributing to the stabilization of PD-1. Upon binding to PD-L1, the intracellular domain of PD-1 undergoes phosphorylation, recruiting SHP2-2 and subsequently initiating immunosuppressive signaling. Lck enhances the phosphorylation of PD-1, intensifying its downstream effects. IL-2 promotes the transcription of FBXO38, which, in turn, binds to the cytoplasmic region of PD-1, facilitating polyubiquitination and subsequent proteasome-mediated degradation. MARCH5, c-Cbl, and FBW7 are also implicated in promoting PD-1 ubiquitination. MDM2 facilitates the interaction between NGLY1 and PD-1, leading to the deglycosylation of PD-1. Furthermore, DHHC9 promoted the palmitoylation of PD-1 to enhance its interaction with Rab11. Inhibition of palmitoylation diminishes the transport of PD-1 to the recycling endosome, promoting its degradation in the lysosome. This process is also associated with a notable enhancement in the interaction between PD-1 and mTOR signal effector proteins (S6K and eIF4E). The black arrows indicate positive regulatory pathways, while the red arrows indicate negative regulatory pathways