NUP-1 is a large coiled-coil nucleoskeletal protein in Trypanosomes with lamin-like functions

Misteli, T. et al. (2012) NUP-1 is a large coiled-coil nucleoskeletal protein in Trypanosomes with lamin-like functions. PLoS Biology, 10(3), e1001287. (doi: 10.1371/journal.pbio.1001287)

[img] Text
64252.pdf
Available under License Creative Commons Attribution.

1MB

Publisher's URL: http://dx.doi.org/10.1371/journal.pbio.1001287

Abstract

A unifying feature of eukaryotic nuclear organization is genome segregation into transcriptionally active euchromatin and transcriptionally repressed heterochromatin. In metazoa, lamin proteins preserve nuclear integrity and higher order heterochromatin organization at the nuclear periphery, but no non-metazoan lamin orthologues have been identified, despite the likely presence of nucleoskeletal elements in many lineages. This suggests a metazoan-specific origin for lamins, and therefore that distinct protein elements must compose the nucleoskeleton in other lineages. The trypanosomatids are highly divergent organisms and possess well-documented but remarkably distinct mechanisms for control of gene expression, including polycistronic transcription and trans-splicing. NUP-1 is a large protein localizing to the nuclear periphery of Trypanosoma brucei and a candidate nucleoskeletal component. We sought to determine if NUP-1 mediates heterochromatin organization and gene regulation at the nuclear periphery by examining the influence of NUP-1 knockdown on morphology, chromatin positioning, and transcription. We demonstrate that NUP-1 is essential and part of a stable network at the inner face of the trypanosome nuclear envelope, since knockdown cells have abnormally shaped nuclei with compromised structural integrity. NUP-1 knockdown also disrupts organization of nuclear pore complexes and chromosomes. Most significantly, we find that NUP-1 is required to maintain the silenced state of developmentally regulated genes at the nuclear periphery; NUP-1 knockdown results in highly specific mis-regulation of telomere-proximal silenced variant surface glycoprotein (VSG) expression sites and procyclin loci, indicating a disruption to normal chromatin organization essential to life-cycle progression. Further, NUP-1 depletion leads to increased VSG switching and therefore appears to have a role in control of antigenic variation. Thus, analogous to vertebrate lamins, NUP-1 is a major component of the nucleoskeleton with key roles in organization of the nuclear periphery, heterochromatin, and epigenetic control of developmentally regulated loci.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Swiderski, Dr Michal and Barry, Professor J
Authors: Misteli, T., DuBois, K.N., Alsford, S., Holden, J.M., Buisson, J., Swiderski, M., Bart, J., Ratushny, A.V., Wan, Y., Bastin, P., Barry, J.D., Navarro, M., Horn, D., Aitchison, J.D., Rout, M.P., and Field, M.C.
College/School:College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN:1544-9173
ISSN (Online):1545-7885
Published Online:27 March 2012
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in PLoS Biology 10(3):e1001287
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
414811Antigenic Variation & Transmission in African TrypanosomesJ BarryWellcome Trust (WELLCOME)055558/Z/98/CInfection Immunity and Inflammation Life Sciences