Moonlighting proteins mediate cross talk between different pathways and cellular control networks. Sometimes, they even coordinate subsequent steps in the same pathway. For this Outlook paper we asked the question, which cellular processes employ multifunctional proteins (MFPs) and what makes them so attractive to cells and organisms. After reviewing their widespread occurrence, we will focus on higher eukaryotic model systems and on few examples that are linked to ongoing work in our laboratory. We will discuss the activities of transcription factor IIH (TFIIH), and its subcomplexes containing Xpd and Cdk7, and we will cover an aminoacyl-tRNA synthetase (LysRS) and DEAD box RNA helicases. Furthermore, we will analyze how cells are able to properly regulate the different biological activities of multifunctional proteins and which advantages such proteins offer to cells and organisms. Finally we also note that the proteins we discuss are linked to tumor formation or recruited by viruses that coopt the multifunctional protein for yet another purpose. 1. Introduction For decades one hypothesis ruled most scientist’s mind: one gene gives rise to one protein, which performs one specific role in the cell. Nowadays, this hypothesis gets severely challenged as there is increasing evidence that many proteins perform multiple functions and many cells seem to exploit the opportunities offered by these multitask proteins. Numerous cellular control processes act simultaneously in the same cell and many proteins function in more than one control process. This realization has spurred our interest in finding out how cells take advantage of such dual- or even multifunctional proteins (MFPs). There are examples of dual roles that appear to be simple evolutionary “duplication steps” (Figure 1). Such MFPs can then be found in different protein complexes, which account for their different biological functions. In other cases, however, MFPs regulate parallel or subsequent cellular processes in a coordinated fashion (Figure 2). This points to a higher level of cellular control associated with the reuse of this protein. In yet other cases two alternative pathways share a component that is present only in limited amounts in the cell and this low abundance allows it to only function in one process at the time (Figure 3). In this case cells may use such a protein as a switch between two alternative processes, regulating them in an inverse manner. Figure 1: Evolutionary duplication steps. MFPs can be found in different complexes, promoting different activities. For example, RPN5
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