Non-canonical role of cancer-associated mutant SEC23B in the ribosome biogenesis pathway

Abstract SEC23B is a component of coat protein complex II (COPII) vesicles that transport secretory proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Loss-of-function SEC23B mutations cause a rare form of anemia, resulting from decreased SEC23B levels. We recently identified germl...

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Bibliographic Details
Published in:Human molecular genetics 2018-09, Vol.27 (18), p.3154-3164
Main Authors: Yehia, Lamis, Jindal, Supriya, Komar, Anton A, Eng, Charis
Format: Article
Language:English
Subjects:
Carcinogenesis - genetics
COP-Coated Vesicles - genetics
Endoplasmic Reticulum - genetics
Endoplasmic Reticulum Stress - genetics
Gene Expression Regulation, Neoplastic
Germ-Line Mutation - genetics
Golgi Apparatus - genetics
Heterozygote
Humans
Loss of Function Mutation - genetics
Neoplasms - genetics
Neoplasms - pathology
Original
Pol1 Transcription Initiation Complex Proteins - genetics
Protein Binding
Ribosomes - genetics
Vesicular Transport Proteins - genetics
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Summary:Abstract SEC23B is a component of coat protein complex II (COPII) vesicles that transport secretory proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Loss-of-function SEC23B mutations cause a rare form of anemia, resulting from decreased SEC23B levels. We recently identified germline heterozygous SEC23B variants as potentially cancer-predisposing. Mutant SEC23B associated with ER stress-mediated tumorigenesis, without decreased SEC23B expression. However, our understanding of the processes behind these observations remain limited. Here, we show mutant SEC23B exists within nucleoli, in addition to classical distribution at the ER/Golgi. This occurs independent of other COPII proteins and does not compromise secretory function. Mutant cells have increased ribosomal protein and translation-related gene expression, and enhanced translational capacity, in the presence of ER stress. We show that mutant SEC23B binds to UBF transcription factor, with increased UBF transcription factor binding at the ribosomal DNA promoter. Our data indicate SEC23B has potential non-canonical COPII-independent function, particularly within the ribosome biogenesis pathway, and that may contribute to the pathogenesis of cancer-predisposition.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddy226