Deconstruction of O-glycosylation-GalNAc-T isoforms direct distinct subsets of the O-glycoproteome

Katrine T Schjoldager, Hiren J Joshi, Yun Kong, Christoffer K Goth, Sarah Louise King-Smith, Hans H Wandall, Eric P Bennett, Sergey Y Vakhrushev, Henrik Clausen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

84 Citationer (Scopus)

Abstract

GalNAc-type O-glycosylation is found on most proteins trafficking through the secretory pathway in metazoan cells. The O-glycoproteome is regulated by up to 20 polypeptide GalNAc-Ts and the contributions and biological functions of individual GalNAc-Ts are poorly understood. Here, we used a zinc-finger nuclease (ZFN)-directed knockout strategy to probe the contributions of the major GalNAc-Ts (GalNAc-T1 and GalNAc-T2) in liver cells and explore how the GalNAc-T repertoire quantitatively affects the O-glycoproteome. We demonstrate that the majority of the O-glycoproteome is covered by redundancy, whereas distinct subsets of substrates are modified by non-redundant functions of GalNAc-T1 and GalNAc-T2. The non-redundant O-glycoproteome subsets and specific transcriptional responses for each isoform are related to different cellular processes; for the GalNAc-T2 isoform, these support a role in lipid metabolism. The results demonstrate that GalNAc-Ts have different non-redundant glycosylation functions, which may affect distinct cellular processes. The data serves as a comprehensive resource for unique GalNAc-T substrates. Our study provides a new view of the differential regulation of the O-glycoproteome, suggesting that the plurality of GalNAc-Ts arose to regulate distinct protein functions and cellular processes.

OriginalsprogEngelsk
TidsskriftE M B O Reports
Vol/bind16
Udgave nummer12
Sider (fra-til)1713-22
Antal sider10
ISSN1469-221X
DOI
StatusUdgivet - dec. 2015

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