PD-1 expression is also regulated post-translationally (2). The PD-1 extracellular domain is
glycosylated at asparagine (N) residues N49 and N72 while in the endoplasmic reticulum. PD-1
subsequently transits to the golgi apparatus where it is fucosylated at the same sites by the
core fucosylase FUT8. This post translational modification represents a novel therapeutic target
as T cells have a more robust anticancer response due to reduced surface expression of
de-fucosylated PD-1. PD-1 is polyubiquinated at lysine (K) residue K48 by the E3 ligase F-Box 38
(FBX028) (2,7) which results in PD-1 degradation via the proteosome.
PD-1 serves as the receptor for programmed death ligand 1 (PD-L1/CD274/B7-H1) and PD-L2
(CD273/B7-DC) (8,9). The interaction of the extracellular domains of PD-1 and PD-L1 causes a
confirmational change that results in the phosphorylation of the cytoplasmic immunoreceptor
tyrosine-based inhibitory motif (ITIM) and the immunoreceptor tyrosine-based switch motif
(ITSM) by Src family kinases (4). Src homology 2 containing tyrosine phosphatase 2 (SHP-2) and
SHP-1 are recruited in order to attenuate T cell activating signals via dephosphorylation of
downstream signaling cascades.
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