Role of linear ubiquitination in inflammatory responses and tissue homeostasis

Abstract

Polyubiquitination is a post-translational modification involved in a wide range of immunological events, including inflammatory responses, immune cell differentiation, and development of inflammatory diseases. The versatile functions of polyubiquitination are based on different types of ubiquitin linkage, which enable various UBD (ubiquitin binding domain)-containing adaptor proteins to associate and induce distinct biological outputs. A unique and atypical type of polyubiquitin chain comprising a conjugation between the N-terminal methionine of the proximal ubiquitin moiety and the C-terminal glycine of the distal ubiquitin moiety, referred to as a linear or M1-linked ubiquitin chain, has been studied exclusively within the field of immunology because it is distinct from other polyubiquitin forms: linear ubiquitin chains are generated predominantly by various inflammatory stimulants, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and act as a critical modulator of transient and optimal signal transduction. Moreover, accumulating evidence suggests that linear ubiquitin chains are of physiological significance. Dysregulation of linear ubiquitination triggers chronic inflammation and immunodeficiency via downregulation of linear ubiquitin-dependent nuclear factor-kappa B (NF-κB) signaling and by triggering TNF-α-induced cell death, suggesting that linear ubiquitination is a homeostatic regulator of tissue-specific functions. In this review, we focus on our current understating of the molecular and cellular mechanisms by which linear ubiquitin chains control inflammatory environments. Furthermore, we review the role of linear ubiquitination on T cell development, differentiation, and function, thereby providing insight into its direct association with maintaining the immune system.

Keywords: LUBAC; T cell; TNF signaling; cell death; inflammation.