ZNT5-6 and ZNT7 play an integral role in protein N-glycosylation by supplying Zn2+ to Golgi α-mannosidase II

Hana Yuasa; Naho Morino; Takumi Wagatsuma; Masayuki Munekane; Sachiko Ueda; Mayu Matsunaga; Yasuo Uchida; Takane Katayama; Toshihiko Katoh; Taiho Kambe

doi:10.1016/j.jbc.2024.107378

ZNT5-6 and ZNT7 play an integral role in protein N-glycosylation by supplying Zn²⁺ to Golgi α-mannosidase II

J Biol Chem. 2024 May 16;300(6):107378. doi: 10.1016/j.jbc.2024.107378. Online ahead of print.

Authors

Affiliations

¹ Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
² Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
³ Department of Molecular Systems Pharmaceutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima City, Japan.
⁴ Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan. Electronic address: kambe.taiho.7z@kyoto-u.ac.jp.

PMID: 38762179
DOI: 10.1016/j.jbc.2024.107378

Abstract

The stepwise addition of monosaccharides to N-glycans attached to client proteins to generate a repertoire of mature proteins involves a concerted action of many glycosidases and glycosyltransferases. Here, we report that Golgi α-mannosidase II (GMII), a pivotal enzyme catalyzing the first step in the conversion of hybrid- to complex-type N-glycans, is activated by Zn²⁺ supplied by the early secretory compartment-resident ZNT5-ZNT6 heterodimers (ZNT5-6) and ZNT7 homodimers (ZNT7). Loss of ZNT5-6 and ZNT7 function results in marked accumulation of hybrid-type and complex/hybrid glycans with concomitant reduction of complex- and high-mannose-type glycans. In cells lacking the ZNT5-6 and ZNT7 functions, the GMII activity is substantially decreased. In contrast, the activity of its homolog, lysosomal mannosidase (LAMAN), is not decreased. Moreover, we show that the growth of pancreatic cancer MIA PaCa-2 cells lacking ZNT5-6 and ZNT7 is significantly decreased in a nude mouse xenograft model. Our results indicate the integral roles of ZNT5-6 and ZNT7 in N-glycosylation and highlight their potential as novel target proteins for cancer therapy.

Keywords: Golgi mannosidase II (GMII); N-glycosylation; ZNT; Zn(2+); early secretory compartments; lysosomal mannosidase (LAMAN); pancreatic cancer cell growth; quality control; transporter; xenograft.