Golgi self-correction generates bioequivalent glycans to preserve cellular homeostasis

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Abstract

Essential biological systems employ self-correcting mechanisms to maintain cellular homeostasis. Mammalian cell function is dynamically regulated by the interaction of cell surface galectins with branched N-glycans. Here we report that N-glycan branching deficiency triggers the Golgi to generate bioequivalent N-glycans that preserve galectin-glycoprotein interactions and cellular homeostasis. Galectins bind N-acetyllactosamine (LacNAc) units within N-glycans initiated from UDP-GlcNAc by the medial-Golgi branching enzymes as well as the trans-Golgi poly-LacNAc extension enzyme β1,3-N-acetylglucosaminyltransferase (B3GNT). Marginally reducing LacNAc content by limiting N-glycans to three branches results in T-cell hyperactivity and autoimmunity; yet further restricting branching does not produce a more hyperactive state. Rather, new poly-LacNAc extension by B3GNT maintains galectin binding and immune homeostasis. Poly-LacNAc extension is triggered by redistribution of unused UDP-GlcNAc from the medial to trans-Golgi via inter-cisternal tubules. These data demonstrate the functional equivalency of structurally dissimilar N-glycans and suggest a self-correcting feature of the Golgi that sustains cellular homeostasis.

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Haik Mkhikian

Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Christie-Lynn Mortales

Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, United States

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The authors declare that no competing interests exist.
Raymond Zhou

Department of Neurology and Institute for Immunology, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Khachik Khachikyan

Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, United States

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The authors declare that no competing interests exist.
Gang Wu

Department of Life Sciences, Imperial College London, London, United Kingdom

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The authors declare that no competing interests exist.
Stuart M Haslam

Department of Life Sciences, Imperial College London, London, United Kingdom

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The authors declare that no competing interests exist.
Patil Kavarian

Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, United States

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The authors declare that no competing interests exist.
Anne Dell

Department of Life Sciences, Imperial College London, London, United Kingdom

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The authors declare that no competing interests exist.
Michael Demetriou

Department of Neurology and Institute for Immunology, University of California, Irvine, Irvine, United States

For correspondence
mdemetri@uci.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2001-2305) of the University of California, Irvine.

Human subjects: Informed consent was obtained from human subjects to obtain peripheral blood for isolation of T cells and that resulting publications and/or presentations will not contain identifiable information. This was approved by the University of California Irvine Institutional Review board (HS#2001-2075).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.