The Multitasking Potential of Alarmins and Atypical Chemokines

Abstract

When the human genome was sequenced, it came as a surprise that it contains "only" 21,306 protein-coding genes. However, complexity and diversity are multiplied by alternative splicing, non-protein-coding transcripts, or post-translational modifications (PTMs) on proteome level. Here, we discuss how the multi-tasking potential of proteins can substantially enhance the complexity of the proteome further, while at the same time offering mechanisms for the fine-regulation of cell responses. Discoveries over the past two decades have led to the identification of "surprising" and previously unrecognized functionalities of long known cytokines, inflammatory mediators, and intracellular proteins that have established novel molecular networks in physiology, inflammation, and cardiovascular disease. In this mini-review, we focus on alarmins and atypical chemokines such as high-mobility group box protein-1 (HMGB-1) and macrophage migration-inhibitory factor (MIF)-type proteins that are prototypical examples of these classes, featuring a remarkable multitasking potential that allows for an elaborate fine-tuning of molecular networks in the extra- and intracellular space that may eventually give rise to novel "task"-based precision medicine intervention strategies.

Keywords: MIF protein family; alarmin; cardiovascular disease; chemokine; cytokine; inflammation; moonlighting; promiscuity.

Figure 1

Scheme summarizing the multitasking/moonlighting functions of HMGB1. For details see manuscript text. HMGB1, high mobility group box-1; HMGB1red, fully reduced HMGB1; HMGB1ox, partially or fully oxidized HMGB1; TLR, Toll-like receptor; RAGE, receptor of advanced glycation endproducts (AGEs); MD2, myeloid differentiation factor 2/lymphocyte antigen 96.

Figure 2

Scheme summarizing the multitasking/moonlighting functions of MIF proteins. For overview purposes, only MIF but not MIF-2/D-DT is depicted. For details see manuscript text. MIF, macrophage migration-inhibitory factor; CSN, COP9 signalosome; Trx, thioredoxin; Prx, peroxiredoxin; SOD, superoxide dismutase; AIF, apoptosis-inducing factor.