**1. Introduction**

Survival of both individuals and a species is predicated, in no small measure, on their ability to respond to a changing environment. Faced with the challenge of drastic changes, organisms have stark options of fight or flight. Flight comes with its own series of challenges (including adapting to a new environment, or competing with others that have already occupied the new niche). Either way there is a strong evolutionary imperative to acquire an ability to adapt. Adaptation is likely to require response at different time scales from immediate (at the level of the individual) to geological scale (at the level of species and genus). Rapid response can be both a benefit and a cost, as a quick change in direction can sometimes prove to be detrimental in the fullness of time and might, therefore, be likely to favor rapid responses that are also readily reversible. Critical decision points used by the organism to drive response in a particular direction need to be robustly integrated into the core physiology of the cell. In this review I argue in favor of the broader interpretation of the term epiproteome to encapsulate the concepts that (1) changes at the post-translational level are ideally placed to respond in real time and that (2) flexible proteins displaying significant disorder are ideal platforms that can be decorated with post-translational changes and used to integrate responses that potentially have competing impacts on cellular resources.

The term epiproteome was first coined by Dai and Rasmussen [1] to refer to proteomic changes directly associated with epigenetic modifications, namely histone acetylation. Some researchers argue that histone modifications are part of epigenetics, although others argue that their lack of heritability means they should not be included in that term. A search for epiproteome/epiproteomics in PubMed Central yields references to post-translational modification (PTM) changes in histones and a small number that use the term in a wider sense to refer to other PTM [2]. Below I argue in favor of the broad interpretation that includes all PTM.

I suggest that an understanding of the epiproteome (i.e., changing alternative post-translational protein states) in combination with the critical nodal positions occupied by disordered proteins, provides a new basis to comprehend the hypervariable PTM theatre. Its features enable integration of multiple post-translational signals to match the demands of a flexible response. The best examples of hypervariable theatres of response to stress are the battle between hosts and their pathogens and/or their changing environment. Epiproteomic changes offer the host an elegant real-time control of its responses. Unfortunately, this also makes the PTM theatre an Achilles heel, able to be exploited by pathogens. Arguably this explains why so much of a pathogens weaponry appears to be enzymatic and focused on the PTM level of host organisation [3].
