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Nat Commun. 2015 Sep 10;6:8218. doi: 10.1038/ncomms9218.

Nuclear envelope-associated endosomes deliver surface proteins to the nucleus.

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Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
Institute of Medical Biology, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648, Singapore.
Joint IMB-IMCB Electron Microscopy Suite, 20 Biopolis Street, #B2-14 Matrix, Singapore 138671, Singapore.
Department of Biochemistry, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore.


Endocytosis directs molecular cargo along three main routes: recycling to the cell surface, transport to the Golgi apparatus or degradation in endolysosomes. Pseudomonas exotoxin A (PE) is a bacterial protein that typically traffics to the Golgi and then the endoplasmic reticulum before translocating to the cytosol. Here we show that a substantial fraction of internalized PE is also located in nuclear envelope-associated endosomes (NAE), which display limited mobility, exhibit a propensity to undergo fusion and readily discharge their contents into the nuclear envelope. Electron microscopy and protein trapping in the nucleus indicate that NAE mediate PE transfer into the nucleoplasm. RNAi screening further revealed that NAE-mediated transfer depends on the nuclear envelope proteins SUN1 and SUN2, as well as the Sec61 translocon complex. These data reveal a novel endosomal route from the cell surface to the nucleoplasm that facilitates the accumulation of extracellular and cell surface proteins in the nucleus.

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