Exploring Non-Metabolic Functions of Glycolytic Enzymes in Immunity

Scott M. Seki, Alban Gaultier

At the beginning of the twentieth century, discoveries in cancer research began to elucidate the idiosyncratic metabolic proclivities of tumor cells (1). Investigators postulated that revealing the distinct nutritional requirements of cells with unchecked growth potential would reveal targetable metabolic vulnerabilities by which their survival could be selectively curtailed. Soon thereafter, researchers in the field of immunology began drawing parallels between the metabolic characteristics of highly proliferative cancer cells and those of immune cells that respond to perceived threats to host physiology by invading tissues, clonally expanding, and generating vast amounts of pro-inflammatory effector molecules to provide the host with protection. Throughout the past decade, increasing effort has gone into elucidating the biosynthetic and bioenergetic requirements of immune cells during inflammatory responses. It is now well established that, like tumor cells, immune cells must undergo metabolic adaptations to fulfill their effector functions (2, 3). Unraveling the metabolic adaptations that license inflammatory immune responses may lead to the development of novel classes of therapeutics for pathologies with prominent inflammatory components (e.g., autoimmunity). However, the translational potential of discoveries made toward this end is currently limited by the ubiquitous nature of the "pathologic" process being targeted: metabolism. Recent works have started to unravel unexpected non-metabolic functions for metabolic enzymes in the context of inflammation, including signaling and gene regulation. One way information gained through the study of immunometabolism may be leveraged for therapeutic benefit is by exploiting these non-canonical features of metabolic machinery, modulating their contribution to the immune response without impacting their basal metabolic functions. The focus of this review is to discuss the metabolically independent functions of glycolytic enzymes and how these could impact T cells, agents of the immune system that are commonly considered as orchestrators of auto-inflammatory processes.