GALNTL5 binds GalNAc and is required for migration through the uterotubal junction and sperm-zona pellucida binding

Taichi Noda; Reika Uriu; Daisuke Mashiko; Hina Shinohara; Yongcun Qu; Ayumu Taira; Ryan M Matzuk; Duri Tahala; Motochika Nakano; Kimi Araki; Zhifeng Yu; Ying Zhang; Martin M Matzuk; Masahito Ikawa

doi:10.1038/s41467-025-63805-4

GALNTL5 binds GalNAc and is required for migration through the uterotubal junction and sperm-zona pellucida binding

Nat Commun. 2025 Sep 17;16(1):8264. doi: 10.1038/s41467-025-63805-4.

Authors

Taichi Noda^#^{1

2

3}, Reika Uriu^#⁴, Daisuke Mashiko⁵, Hina Shinohara⁴, Yongcun Qu⁶, Ayumu Taira⁴, Ryan M Matzuk⁷, Duri Tahala⁴, Motochika Nakano⁴, Kimi Araki^{4

8}, Zhifeng Yu⁷, Ying Zhang⁹, Martin M Matzuk¹⁰, Masahito Ikawa^{11

12

13

14}

Affiliations

¹ Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan. noda-t@kumamoto-u.ac.jp.
² Priority Organization for Innovation and Excellence, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto, Japan. noda-t@kumamoto-u.ac.jp.
³ Research Institute for Microbial Diseases, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka, Japan. noda-t@kumamoto-u.ac.jp.
⁴ Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan.
⁵ Research Institute for Microbial Diseases, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka, Japan.
⁶ Institute of Artificial Intelligence in Sports (IAIS), Capital University of Physical Education and Sports, Beijing, P. R. China.
⁷ Center for Drug Discovery and Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
⁸ Center for Metabolic Regulation of Healthy Aging, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, Japan.
⁹ The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China.
¹⁰ Center for Drug Discovery and Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA. mmatzuk@bcm.edu.
¹¹ Research Institute for Microbial Diseases, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka, Japan. ikawa@biken.osaka-u.ac.jp.
¹² The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan. ikawa@biken.osaka-u.ac.jp.
¹³ Center for Infectious Disease Education and Research (CiDER), The University of Osaka, Suita, Osaka, Japan. ikawa@biken.osaka-u.ac.jp.
¹⁴ Center for Advanced Modalities and DDS (CAMaD), The University of Osaka, Suita, Osaka, Japan. ikawa@biken.osaka-u.ac.jp.

^# Contributed equally.

Abstract

More than 20 genes expressed in the male reproductive tract have been identified as essential factors for sperm migration to and through the utero-tubal junction (UTJ), and they are divided into ADAM3-dependent and ADAM3-independent pathways. In parallel, sperm having UTJ migration defects also show impaired binding to the zona pellucida (ZP). Herein, we demonstrate that knockout of Galntl5, encoding a sperm surface protein, causes impaired sperm binding with the UTJ and ZP, and null males have severe infertility. GALNTL5 appreciably disappears in sperm lacking Adam3 or Lypd4, required for ADAM3-dependent and ADAM3-independent pathways, and GALNTL5 binds to N-acetylgalactosamine (GalNAc) distributed on the UTJ and ZP. Blockage of GalNAc decreases the number of sperm binding to the UTJ and ZP. Thus, we unveil that GALNTL5 is a responsible factor for UTJ migration and sperm-ZP binding, and that sperm bind to the UTJ and ZP through interaction of GALNTL5 and GalNAc.

MeSH terms

ADAM Proteins
Acetylgalactosamine* / metabolism
Animals
Fallopian Tubes* / metabolism
Female
Humans
Infertility, Male / genetics
Infertility, Male / metabolism
Lectins* / genetics
Lectins* / metabolism
Male
Membrane Glycoproteins
Mice
Mice, Knockout
N-Acetylgalactosaminyltransferases* / genetics
N-Acetylgalactosaminyltransferases* / metabolism
Polypeptide N-acetylgalactosaminyltransferase
Protein Binding
Sperm Motility
Sperm-Ovum Interactions* / physiology
Spermatozoa* / metabolism
Uterus* / metabolism
Zona Pellucida* / metabolism

Substances

Acetylgalactosamine
N-Acetylgalactosaminyltransferases
Lectins
Adam3 protein, mouse
Polypeptide N-acetylgalactosaminyltransferase
Membrane Glycoproteins
ADAM Proteins

Abstract

MeSH terms

Substances

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