Endoplasmic Reticulum-Associated Degradation-Dependent Processing in Cross-Presentation and Its Potential for Dendritic Cell Vaccinations: A Review

Abstract

While the success of dendritic cell (DC) vaccination largely depends on cross-presentation (CP) efficiency, the precise molecular mechanism of CP is not yet characterized. Recent research revealed that endoplasmic reticulum (ER)-associated degradation (ERAD), which was first identified as part of the protein quality control system in the ER, plays a pivotal role in the processing of extracellular proteins in CP. The discovery of ERAD-dependent processing strongly suggests that the properties of extracellular antigens are one of the keys to effective DC vaccination, in addition to DC subsets and the maturation of these cells. In this review, we address recent advances in CP, focusing on the molecular mechanisms of the ERAD-dependent processing of extracellular proteins. As ERAD itself and the ERAD-dependent processing in CP share cellular machinery, enhancing the recognition of extracellular proteins, such as the ERAD substrate, by ex vivo methods may serve to improve the efficacy of DC vaccination.

Targeting ubiquitin signaling for cancer immunotherapy

“…14 Similarly, overexpression of a dominant-negative ubiquitin mutant lacking all of the lysine residues in mammalian cells abrogates polyubiquitination and potently inhibits MHC I-restricted processing of endoplasmic reticulum (ER)-targeted proteins. 15 Accumulating evidence suggests that MHC I-restricted processing of exogenous proteins for cross-presentation involves ER-associated degradation (ERAD), [16][17][18][19] a mechanism mediating retrotranslocation of misfolded proteins from the ER back to the cytoplasm for proteasomal degradation. 20 ERAD also mediates processing of extracellular proteins involved in antigen cross-presentation.…”

“…20 ERAD also mediates processing of extracellular proteins involved in antigen cross-presentation. 19 Thus, approaches to enhance ER entry of protein antigens, such as Grp170 chaperone-based vaccine adjuvant system, improve the efficiency of cross-presentation and induction of CD8 T cell responses in cancer immunotherapy. 19,21 Ubiquitination has a vital role in ERAD-dependent protein processing.…”

“…19 Thus, approaches to enhance ER entry of protein antigens, such as Grp170 chaperone-based vaccine adjuvant system, improve the efficiency of cross-presentation and induction of CD8 T cell responses in cancer immunotherapy. 19,21 Ubiquitination has a vital role in ERAD-dependent protein processing. It is thought that ubiquitination of ERAD substrates facilitates their binding by the ERAD molecular machinery required for their retrotranslocation to the cytoplasm.…”

Targeting endoplasmic reticulum associated degradation pathway combined with radiotherapy enhances the immunogenicity of esophageal cancer cells

“… 17 Then, the ERAD pathway was activated and involved in misfolded protein degradation to alleviate ER stress. 18 Previous study demonstrated that RT alone was capable of inducing mild ER stress. 19 Enhanced and prolonged ER stress was able to amplify ICD-associated immunogenicity in cancer; in contrast, weak or mild ER stress could be mitigated by the activation of ERAD pathway and had limited efficacy in triggering ICD.…”

“… 19 Enhanced and prolonged ER stress was able to amplify ICD-associated immunogenicity in cancer; in contrast, weak or mild ER stress could be mitigated by the activation of ERAD pathway and had limited efficacy in triggering ICD. 18 , 20 Thereby, targeting ERAD pathway may enhance radiation-induced ER stress and improve the immunogenicity of tumor cells. In recent years, several chemotherapeutic agents have been depicted to trigger ICD in various tumor models; however, the commonly used cytotoxic drugs in EC including fluorouracil and cisplatin were inefficient to induce ICD.…”