title: The C-Box Region of MAF1 Regulates Transcriptional Activity and Protein Stability.
abstract: MAF1 is a conserved negative regulator of RNA polymerase (pol) III and intracellular lipid homeostasis across species. Here, we show that the MAF1 C-box region negatively regulates its activity. Mutations in Caenorhabditis elegans mafr-1 that truncate the C-box retain the ability to inhibit the transcription of RNA pol III targets, reduce lipid biogenesis, and lower reproductive output. In human cells, C-box deletion of MAF1 leads to increased MAF1 nuclear localization and enhanced repression of ACC1 and FASN, but with impaired repression of RNA pol III targets. Surprisingly, C-box mutations render MAF1 insensitive to rapamycin, further defining a regulatory role for this region. Two MAF1 species, MAF1Land MAF1S, are regulated by the C-box YSY motif, which, when mutated, alters species stoichiometry and proteasome-dependent turnover of nuclear MAF1. Our results reveal a role for the C-box region as a critical determinant of MAF1 stability, activity, and response to cellular stress.
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Pradhan
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Department of Molecular and Computational Biology, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Hammerquist
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Department of Molecular and Computational Biology, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Akshat
authors.initials: A
authors.lastname: Khanna
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Department of Molecular and Computational Biology, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: spcurran@usc.edu.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Curran
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D055550:Protein Stability; D012320:RNA Polymerase III / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D029742:Caenorhabditis elegans Proteins; C000599610:MAFR-1 protein, C elegans; D012097:Repressor Proteins; D012320:RNA Polymerase III; D020123:Sirolimus
keywords: Caenorhabditis elegans; MAF1; RNA polymerase III; lipid metabolism; mTOR