Cross Talk between Cellular Regulatory Networks Mediated by Shared Proteins

Abstract

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.

Double-sieving-defective aminoacyl-tRNA synthetase causes protein mistranslation and affects cellular physiology and development

“…Mutations in cytoplasmic glycyl-tRNA synthetase (GlyRS), tyrosyl-tRNA synthetase (TyrRS), lysyl-tRNA synthetase (LysRS) and alanyl-tRNA synthetase (AlaRS) have been shown to be associated with Charcot-Marie-Tooth (CMT) disease, one of the most common inherited neurological disorders 6 7 8 9 . However, how these mutations relate to the disease phenotypes has remained unclear, although impaired aminoacylation activity and loss of non-canonical functions of the aaRSs have been proposed as possible mechanisms 4 5 10 . Here we describe a fine-tuning mechanism of aminoacylation accuracy, the failure of which can dramatically reduce translation fidelity and affect cellular function.…”

An aminoacylation independent activity of PheRS/FARS promotes growth and proliferation

“…PheRS, TrpRS, and LeuRS are not the only aaRS family member with roles beyond charging tRNAs (Dolde et al, 2014;Guo et al, 2010;Lu et al, 2015;Pang et al, 2014). For instance, MetRS/MRS is capable of stimulating rRNA synthesis (Ko et al, 2000), GlnRS/QRS can block the kinase activity of apoptosis signal-regulating kinase 1 (ASK1) (Ko et al, 2001) and a proteolytically processed form of YARS/TyrRS acts as a cytokine (Casas-Tinto et al, 2015;Greenberg et al, 2008).…”

“…aaRSs are, however, also not the only protein family which evolved to carry out more than one function. In recent years, it has become increasingly evident that many, if not most, proteins have evolved to carry out not only one, but two or more functions, providing interesting challenges to figure out, which of their activities are important for the specific function of a gene (Dolde et al, 2014).…”

α-Phenylalanyl tRNA synthetase competes with Notch signaling through its N-terminal domain

“…PheRS is not the only aaRS family member with roles beyond charging tRNAs (Dolde et al, 2014). For instance, MetRS/MRS is capable of stimulating rRNA synthesis (Ko et al, 2000), GlnRS/QRS can block the kinase activity of apoptosis signal-regulating kinase 1 (ASK1) (Ko et al, 2001) and a proteolytically processed form of YARS/TyrRS acts as a cytokine (Casas-Tinto et al, 2015;Greenberg et al, 2008).…”

“…aaRSs are, however, also not the only protein family which evolved to carry out more than one function. In recent years it has become increasingly evident that many if not most proteins have evolved to carry out not only one, but two or more functions, providing interesting challenges to figure out, which of their activities are important for the individual functions of a protein (Dolde et al, 2014).…”