Recent Findings in the Posttranslational Modifications of PD-L1

Table 1

Summary of PTMs of PD-L1.

PTMs	Regulators	PTMs site	Mechanism	Therapeutic strategies	Reference
Phosphorylation	AMPK (metformin-activated)	S195	Abnormal glycosylation of PD-L1 and then PD-L1 ubiquitination and degradation	Metformin + anti-CTLA-4	[12]
	JAK1 (IL-6-activated)	Y112	P-Y112 recruits STT3A to catalyze N-glycosylation, preventing the ubiquitination of PD-L1	IL-6 antibody + Tim-3	[15]
	GSK3β (inactivated by EGF/ EGFR, PARP, or c-met)	T180 and S184	Glycosylations of N192/200/219 antagonize PD-L1 and GSK3β interaction, and the P-T180/S184 triggers interaction with E3 ligase β-TrCP	PRAP or c-met inhibitor	[14, 44]
Glycosylation	Sigma1	Cochaperones	Facilitates glycosylated PD-L1	IPAG	[23]
	FKBP51s	Cochaperones	Facilitates glycosylated PD-L1	SAFit	[24]
	B3GNT3	N192 and N200	Stimulates PD-L1 glycosylation, and prevents PD-L1 from internalization and degradation via lysosomes	gPD-L1 antibody-drug conjugate	[21]
	STT3	N35, N192, N200, and N219	Stimulates PD-L1 glycosylation, and prevents PD-L1 from internalization and degradation via lysosomes	Etoposide + Tim-3	[26]
Ubiquitination	β-TrCP	D/LSGXXS	Polyubiquitinate nonglycosylated PD-L1 leading to degradation of PD-L1	Resveratrol	[13]
	E3 ligase HRD1		Recognizes abnormal glycosylation of PD-L1, and promotes its degradation in ERAD	Metformin + anti-CTLA-4	[12]
	E3 ligase SPOP (E3 ligase CDK4)		Degradation of PD-L1	CDK4/6 inhibitor palbociclib or ribociclib	[32]
	E3 ligase STUB1 (upregulated by CMTM6/4)		Degradation of PD-L1	CMTM6 depletion	[30, 31]
	CSN5 (activated by TNF-α and NF-κB)		Removes ubiquitination of PD-L1 and inhibits degradation	Curcumin + anti-CTLA-4	[29]
	USP9X		Protects PD-L1 from ubiquitination and degradation		[33]
Palmitoylation	DHHC3/9	Cys272	Inhibits ubiquitination, and protects PD-L1 from degradation by lysosomes	2-bromopalmitate	[39]