Ubiquitin-like Proteins in Autoimmune Diseases: Current Evidence and Therapeutic Opportunities

Autoimmune diseases encompass a diverse group of disorders characterized by misdirected immune responses against own tissues and organs. In recent decades, the prevalence of autoimmune diseases has steadily increased. Although anti-inflammatory treatments are highly effective for autoimmune diseases, they also cause immunosuppression, leading to an increased risk of cancers and opportunistic infections. Moreover, current treatments primarily focus on suppressing inflammation rather than addressing the underlying causes. Therefore, a comprehensive understanding of the molecular and cellular events within the affected cells is crucial for the development of treatments. Ubiquitin plays a critical role in maintaining cellular homeostasis through processes such as target protein degradation, protein trafficking, and receptor-mediated endocytosis through the E1-E2-E3 cascade. In addition, several ubiquitin-like proteins (UBLs), which share structural similarities with ubiquitin, participate in E1-E2-E3 cascade-mediated processes, thereby expanding the regulatory landscape. Among these UBLs, small ubiquitin-like modifier, interferon-stimulated gene 15, neural precursor cell expressed developmentally down-regulated protein 8, and human leukocyte antigen-F adjacent transcript 10 play distinct roles in the immune system. This review highlights the roles of UBLs in the development of autoimmune diseases. Understanding these functions provides novel insights into molecular mechanisms underlying the development of autoimmune diseases.