MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation
PD-L1/PD-1 immune therapy for the treatment of cancer has shown tremendous promise; however, there are growing examples of poor response and drug resistance. Many studies have been performed to better understand how PD-L1 is regulated at the genetic, transcription, and translational levels. Recent data by Wang et al. identified a mechanism by which monoubiquitination of PD-L1 via MTSS1/AIP4 dependent mechanisms is critical for PD-L1 expression and lung adenocarcinoma immune evasion. Utilizing immune-compromised mouse models, the group showed that MTSS1 suppressed lung adenocarcinoma progression in a host-immunity-dependent fashion. They then identified PD-L1 changes as a critical mechanism by which MTSS1 regulated host immunity. Utilizing MTSS1 knockdown and overexpression in cultured cells, they effectively measured its effect on PD-L1 expression. Control of PD-L1 expression occurred at the protein level through the regulation of lysosomal degradation. This led them to investigate whether MTSS1 controlled the ubiquitination state of PD-L1 and identified monoubiquitination of PD-L1 at lysine 263 as an essential modification. Importantly, AIP4 was identified as the critical E3 ubiquitin ligase that is recruited by MTSS1. Additional studies showed that EGFR/Ras signaling could alter MTSS1 levels to control PD-L1 and immune surveillance. Finally, the group utilized combinatorial drugs to enhance immune checkpoint blockade, which suppressed lung adenocarcinoma progression in immune-compromised mouse models. Cytoskeleton Inc’s studies on PD-L1 ubiquitination using the Signal-Seeker™ Ubiquitination Detection Kit (Cat. # BK161) played a critical role in identifying this critical post-translational modification of a key, immune checkpoint protein.
Above: Schematic showing the mechanism by which EGFR/Ras signaling can suppress MTSS1 as a mechanism to control PD-L1 monoubiquitination and its lysosomal degradation to control immune surveillance.
Link to Citation:
Wang Y. et al. MTSS1 curtails lung adenocarcinoma immune evasion by promoting AIP4-mediated PD-L1 monoubiquitination and lysosomal degradation. Cell Discov. 2023 Feb 21;9(1):20. doi: 10.1038/s41421-022-00507-x.
Middleton-Davis F et al. Method for detecting acetylated PD-L1 in cell lysates by immunoprecipitation and western blot analysis. PLoS One. 2022 Jul 18;17(7):e0268887. doi: 10.1371/journal.pone.0268887.
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