Heregulin, a new interactor of the telosome/shelterin complex in human telomeres.
Telomere length, shape and function depend on a complex of six core telomere-associated proteins referred to as the telosome or shelterin complex. We here demonstrate that the isoform β2 of the heregulin family of growth factors (HRGβ2) is a novel interactor of the telosome/shelterin complex in human telomeres. Analysis of protein-protein interactions using a high-throughput yeast two-hybrid (Y2H) screen identified RAP1, the only telomere protein that is conserved from yeasts to mammals, as a novel interacting partner of HRGβ2. Deletion analysis of RAP1 revealed that the linker domain, a region previously suggested to recruit negative regulators of telomere length, interacts specifically with HRGβ2. Co-immunoprecipitation and imaging experiments demonstrated that, in addition to RAP1, HRGβ2 could associate with the RAP1-associated telomeric repeat binding factor 2 (TRF2). Deletion analysis of HRGβ2 confirmed that a putative nuclear localization signal (NLS) was necessary for nuclear HRGβ2 to exert a negative regulation of telomere length whereas the N-terminus (extracellular) amino acids of HRGβ2 were sufficient to interact with RAP1/TRF2 and promote telomere shortening. Taken together, our studies identify nuclear HRGβ2 as one of the previously unknown regulators predicted to be recruited by the RAP1 linker domain to negatively regulate telomere length in human cells. Our current findings reveal that a new, but likely not the last, unexpected visitor has arrived to the "telosome/shelterin town".
ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology (ICO), Girona, Spain.|Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
Javier A
JA
Menendez
Evanston Northwestern Healthcare Research Institute, Evanston, IL, USA.
Louisa
L
Benboudjema
IBYME, CONICET-Laboratorio de Immunohematología, Buenos Aires, Argentina.
Luciano
L
Vellon
Laboratory of Hematology Service, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Miguel A
MA
Rubio
Department of Biochemistry, University of Mississippi, Jackson, MS, USA.|Cancer Institute, University of Mississippi, Jackson, MS, USA.
Ingrid
I
Espinoza
Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA, USA.|Buck Institute for Research on Aging, Novato, CA, USA.
Judith
J
Campisi
Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA.|Mayo Clinic Cancer Center, Rochester, MN, USA.
Ruth
R
Lupu
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D009154:Mutation; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D059506:Telomere Shortening / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D020890:Neuregulin-1; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; C087230:heregulin beta1
TRF2; heregulin; shelterin complex; telomere; telosome