Sorting nexin 6 enhances lamin a synthesis and incorporation into the nuclear envelope

Jose M González-Granado; Ana Navarro-Puche; Pedro Molina-Sanchez; Marta Blanco-Berrocal; Rosa Viana; Jaime Font de Mora; Vicente Andrés

doi:10.1371/journal.pone.0115571

Sorting nexin 6 enhances lamin a synthesis and incorporation into the nuclear envelope

PLoS One. 2014 Dec 23;9(12):e115571. doi: 10.1371/journal.pone.0115571. eCollection 2014.

Authors

Jose M González-Granado¹, Ana Navarro-Puche¹, Pedro Molina-Sanchez¹, Marta Blanco-Berrocal¹, Rosa Viana², Jaime Font de Mora³, Vicente Andrés¹

Affiliations

¹ Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
² Instituto de Biomedicina de Valencia (IBV), Consejo Superior de Investigaciones Científicas, Valencia, Spain.
³ Fundación para la Investigación Hospital La Fe, and Instituto Valenciano de Patología, Facultad de Medicina, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain.

Abstract

Nuclear lamins are important structural and functional proteins in mammalian cells, but little is known about the mechanisms and cofactors that regulate their traffic into the nucleus. Here, we demonstrate that trafficking of lamin A, but not lamin B1, and its assembly into the nuclear envelope are regulated by sorting nexin 6 (SNX6), a major component of the retromer that targets proteins and other molecules to specific subcellular locations. SNX6 interacts with lamin A in vitro and in vivo and links it to the outer surface of the endoplasmic reticulum in human and mouse cells. SNX6 transports its lamin A cargo to the nuclear envelope in a process that takes several hours. Lamin A protein levels in the nucleus augment or decrease, respectively, upon gain or loss of SNX6 function. We further show that SNX6-dependent lamin A nuclear import occurs across the nuclear pore complex via a RAN-GTP-dependent mechanism. These results identify SNX6 as a key regulator of lamin A synthesis and incorporation into the nuclear envelope.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Endoplasmic Reticulum / metabolism
Endosomes / metabolism
Humans
Lamin Type A / biosynthesis*
Mice
Nuclear Envelope / metabolism*
Proteasome Endopeptidase Complex / metabolism
Protein Binding
Protein Biosynthesis
Protein Transport
Proteolysis
RNA, Messenger / genetics
RNA, Messenger / metabolism
Sorting Nexins / metabolism*
Subcellular Fractions / metabolism
ran GTP-Binding Protein / metabolism

Substances

Lamin Type A
RNA, Messenger
SNX6 protein, human
SNX6 protein, mouse
Sorting Nexins
Proteasome Endopeptidase Complex
ran GTP-Binding Protein

Grants and funding

Work in VA's laboratory is supported by the Ministerio de Economía y Competitividad (MINECO) and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2010-16044), Instituto de Salud Carlos III (ISCIII) (RD12/0042/0028), The Progeria Research Foundation, and the European Commission (Grant No 317916-Liphos). JMGG received salary support from the Sara Borrell and Miguel Servet (CP11/00145) ISCIII programs. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by MINECO and Fundación Pro-CNIC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.