Emerging Roles for Maf1 beyond the Regulation of RNA Polymerase III Activity

Abstract

Maf1 was first identified in yeast, and studies in metazoans have primarily focused on examining its role in the repression of transcription that is dependent on RNA polymerase III. Recent work has revealed a novel and conserved function for Maf1 in the maintenance of intracellular lipid pools in Caenorhabditis elegans, mice, and cancer cell lines. Although additional Maf1 targets are likely, they have not been identified, and these recent findings begin to define specific activities for Maf1 in multicellular organisms beyond the regulation of RNA polymerase III transcription and suggest that Maf1 plays a more diverse role in organismal physiology. We will discuss these newly defined physiological roles of Maf1 that point to its placement as an important new player in lipid metabolism with implications in human metabolic diseases such as obesity and cancer, which display prominent defects in lipid homeostasis.

Keywords: Caenorhabditis elegans; Drosophila melanogaster; RNA polymerase III; human; mouse.

Fig. 1. Maf1 protein structure

A. Maf1 protein sequences in different species share regions of high similarity - A, B and C box regions. Putative and defined NLS sequences are labeled. B. Alignment of CtNLS sequences. Hs- Homo sapiens, Mm- Mus musculus, Dm-Drosophila melanogaster, Ce- Caenorhabditis elegans, Sc- Saccharomyces cerevisiae.

Fig. 2. Model of Maf1 signaling for inhibition of RNA pol I, II, and III

Maf1 integrates nutrient and stress signals to growth by regulating RNA pol III activity. Insulin signaling activates PI3K, which in turn activates members of the AGC kinase gene family. PKA (Protein kinase A) and Sch9 (Serine/threonine-protein kinase) phosphorylate Maf1 to inhibit Maf1 activity. Nutrient deprivation or treatment with Rapamycin inhibits TORC1, which leads to the activation of Maf1. PKC (Protein kinase C) is required for Maf1 dephosphorylation by an unknown mechanism. PP4 (Protein phosphates 4) and PP2A (Protein phosphates 2A) can activate Maf1 by facilitating its dephosphorylating. FoxO1 transcriptionally regulates Maf1 (only observed in C. elegans) and post-translationally by an unknown mechanism. Regulation in mammals is illustrated in grey and cases only seen in yeast are colored blue. Dotted lines and “?” denote documented regulation of Maf1 that occur through unknown mechanisms.

Fig. 3. Future perspectives on Maf1

The multitude of roles for Maf1 in organismal physiology are only starting to be fully uncovered. The figure identifies key questions that will significantly improve our understanding of the diversity of Maf1 functions at the molecular level and organismal levels.