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  • Given the link between E s autoimmunity


    Given the link between E3s, autoimmunity, and antitumor immunity, it DNQX disodium salt is reasonable to assume that, similar to other ICBs, IRAEs may limit the clinical use of E3-targeting therapies – further stressing the need to better understand the underlying mechanisms of these unwanted effects. Despite clinical experience, biomarkers that predict IRAEs associated with CTLA-4-, PD-1-, and PD-L1-targeted therapies deserve further studies (Box 1). Notably, IRAEs occur in only a subset of ICB-treated patients. The selectivity may be attributed to interindividual variation in germline-encoded genetic factors, although analysis of HLA-A*0201 genotypes among advanced melanoma patients treated with CTLA4-blocking antibody did not identify a significant association with IRAE occurrence [96]. The gut microbiome may help in predicting IRAE emergence after ICB treatment: select commensal Bacteroidetes strains were shown to elicit protective effects against CTLA-4-blockade-induced colitis [97], and transfer of bifidobacteria to anti-CTLA-4-treated mice mitigates colitis independently of antitumor immunity [98]. Given that changes in E3 activities impact on autoimmune responses and sometimes promote IRAE-like phenotypes, understanding their function in this context may suggest therapeutic options to mitigate IRAE after ICB.
    Concluding Remarks and Future Perspectives Ubiquitin ligases serve as central regulatory nodes of signaling pathways and elicit selective functions because they may be (i) mutated/dysfunctional in a tumor [9], (ii) expressed in select tissues, and (iii) target specific substrates in a spatial and temporal manner. Thus, they may allow regulatory modules in the immune, tumor, or stromal compartments to be distinguished, and may thus become favorable targets for the selective manipulation of a given pathway in a tissue-/cell type-dependent manner. This review has focused on a relative small fraction of ubiquitin ligases that are expected to play a role in antitumor immunity and autoimmunity. Some were only partially studied, for example Roquin (Table 1), which has been implicated in autoimmunity, but the catalytic activity of its E3 ligase domain has not been studied in this context, and others remain to be identified and characterized. Nevertheless, the emerging theme reflects the important role that E3s play in immune homeostasis, and the topic will become more translationally relevant when better mechanistic and clinical data become available (see Outstanding Questions). A better appreciation of the greater landscape of ubiquitin ligases in the regulation of the immune system and its function in health and disease will allow a higher-resolution map to be established, as well as the identification of the most prevalent targets for therapeutic exploitation in monotherapies or combination therapies.
    Acknowledgments The authors gratefully acknowledge funding by National Cancer Institute (NCI) Outstanding Investigator Awards R35CA197465, R01CA216187 and Department of Defense (DOD) grant CA171013 (to Z.A.R.), Melanoma Research Alliance grant 571135, and DOD grant CA171198 (to R.T.), and a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad (to Y.F.).
    The pathophysiology of heart failure is complex and still poorly understood, though it is a leading cause of mortality worldwide , . The past few decades witnessed exhilarating efforts from researchers across the globe to uncover multiple signaling molecules and pathways that metamorphose gene expression in cardiac hypertrophy and failure, including the prototypical induction of the “embryonic” pro-hypertrophic gene program , , . Only recently, however, protein homeostasis as a key cellular process has caught attention in the context of heart failure and cardiomyopathy. Malfunctioning in protein quality control (PQC) due to extrinsic and/or intrinsic factors such as genetic mutations, ageing, hypertension, biomechanical stress, etc. may result in continued presence and chronic accumulation of misfolded proteins leading to protein aggregation and/or the formation of soluble peptides that are proteotoxic. This in turn precipitates a downward spiral of the cell\'s ability to maintain homeostasis and may eventually result in cell death. Such protein misfolding has been reported to culminate in terminal neurodegeneration diseases like Alzheimer\'s and Huntington\'s , type II diabetes, , and cancers . In recent times, a growing number of cardiac and skeletal muscle diseases have been reported to feature depositions of misfolded proteins, including cardiac amyloidosis, desmin-related cardiomyopathy (DRM), and dilated cardiomyopathy , . Therefore, the clearance of misfolded proteins is equally important for cellular homeostasis.