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Autophagy proteins control goblet cell function by potentiating reactive oxygen species production

Khushbu K Patel, Hiroyuki Miyoshi, Wandy L Beatty, Richard D Head, Nicole P Malvin, Ken Cadwell, Jun‐Lin Guan, Tatsuya Saitoh, Shizuo Akira, Per O Seglen, Mary C Dinauer, Herbert W Virgin, Thaddeus S Stappenbeck

Author Affiliations

  1. Khushbu K Patel1,
  2. Hiroyuki Miyoshi1,
  3. Wandy L Beatty2,
  4. Richard D Head3,
  5. Nicole P Malvin1,
  6. Ken Cadwell4,
  7. Jun‐Lin Guan5,
  8. Tatsuya Saitoh6,
  9. Shizuo Akira6,
  10. Per O Seglen7,
  11. Mary C Dinauer1,8,
  12. Herbert W Virgin1 and
  13. Thaddeus S Stappenbeck*,1
  1. 1 Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
  2. 2 Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA
  3. 3 Department of Genetics, Washington University School of Medicine, St Louis, MO, USA
  4. 4 Department of Microbiology, Skirball Institute, New York University School of Medicine, New York, NY, USA
  5. 5 Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
  6. 6 Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
  7. 7 Prostate Cancer Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
  8. 8 Department of Pediatrics. Washington University School of Medicine, St Louis, MO, USA
  1. *Corresponding author. Department of Pathology and Immunology, Washington University School of Medicine, Box 8118, 660 South Euclid Avenue, St Louis, MO 63110, USA. Tel.:+1 314 362 4214; Fax:+1 314 362 7487; E-mail: stappenb{at}wustl.edu
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Abstract

Delivery of granule contents to epithelial surfaces by secretory cells is a critical physiologic process. In the intestine, goblet cells secrete mucus that is required for homeostasis. Autophagy proteins are required for secretion in some cases, though the mechanism and cell biological basis for this requirement remain unknown. We found that in colonic goblet cells, proteins involved in initiation and elongation of autophagosomes were required for efficient mucus secretion. The autophagy protein LC3 localized to intracellular multi‐vesicular vacuoles that were consistent with a fusion of autophagosomes and endosomes. Using cultured intestinal epithelial cells, we found that NADPH oxidases localized to and enhanced the formation of these LC3‐positive vacuoles. Both autophagy proteins and endosome formation were required for maximal production of reactive oxygen species (ROS) derived from NADPH oxidases. Importantly, generation of ROS was critical to control mucin granule accumulation in colonic goblet cells. Thus, autophagy proteins can control secretory function through ROS, which is in part generated by LC3‐positive vacuole‐associated NADPH oxidases. These findings provide a novel mechanism by which autophagy proteins can control secretion.

There is a Have you seen? (December 2013) associated with this Article.

  • Received April 30, 2013.
  • Accepted September 20, 2013.
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