A novel cysteine-rich adaptor protein is required for mucin packaging and secretory granule stability in vivo

Author:

Zhang Liping1ORCID,Muirhead Kayla J.12,Syed Zulfeqhar A.13ORCID,Dimitriadis Emilios K.4ORCID,Ten Hagen Kelly G.1ORCID

Affiliation:

1. Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892-4370

2. Ambry Genetics, Aliso Viejo, CA 92656

3. Electron Microscopy Core Facility, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892

4. Trans-NIH Resource on Biomedical Engineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD 20892

Abstract

Mucins are large, highly glycosylated extracellular matrix proteins that line and protect epithelia of the respiratory, digestive, and urogenital tracts. Previous work has shown that mucins form large, interconnected polymeric networks that mediate their biological functions once secreted. However, how these large matrix molecules are compacted and packaged into much smaller secretory granules within cells prior to secretion is largely unknown. Here, we demonstrate that a small cysteine-rich adaptor protein is essential for proper packaging of a secretory mucin in vivo. This adaptor acts via cysteine bonding between itself and the cysteine-rich domain of the mucin. Loss of this adaptor protein disrupts mucin packaging in secretory granules, alters the mobile fraction within granules, and results in granules that are larger, more circular, and more fragile. Understanding the factors and mechanisms by which mucins and other highly glycosylated matrix proteins are properly packaged and secreted may provide insight into diseases characterized by aberrant mucin secretion.

Funder

HHS | NIH | National Institute of Dental and Craniofacial Research

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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