Dev Cell. 2019 Oct 7;51(1):7-20.e6.

Jieun Park¹, Daniel S Levic², Kaelyn D Sumigray³, Jennifer Bagwell², Oznur Eroglu², Carina L Block⁴, Cagla Eroglu⁵, Robert Barry⁶, Colin R Lickwar⁷, John F Rawls⁷, Stephen A Watts⁶, Terry Lechler⁸, Michel Bagnat⁹

1. Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
2. Department of Cell Biology, Duke University, Durham, NC 27710, USA.
3. Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
4. Department of Psychology and Neuroscience, Duke University, Durham, NC 27710, USA.
5. Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Neurobiology, Duke University, Durham, NC 27710, United States; Regeneration Next Initiative, Duke University, Durham, NC 27710, United States.
6. Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
7. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
8. Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Dermatology, Duke University Medical Center, Durham, NC 27710, USA.
9. Department of Cell Biology, Duke University, Durham, NC 27710, USA; Regeneration Next Initiative, Duke University, Durham, NC 27710, United States. Electronic address: michel.bagnat@duke.edu.

Abstract

The guts of neonatal mammals and stomachless fish have a limited capacity for luminal protein digestion, which allows oral acquisition of antibodies and antigens. However, how dietary protein is absorbed during critical developmental stages when the gut is still immature is unknown. Here, we show that specialized intestinal cells, which we call lysosome-rich enterocytes (LREs), internalize dietary protein via receptor-mediated and fluid-phase endocytosis for intracellular digestion and trans-cellular transport. In LREs, we identify a conserved endocytic machinery, composed of the scavenger receptor complex Cubilin/Amnionless and Dab2, that is required for protein uptake by LREs and for growth and survival of larval zebrafish. Moreover, impairing LRE function in suckling mice, via conditional deletion of Dab2, leads to stunted growth and severe protein malnutrition reminiscent of kwashiorkor, a devastating human malnutrition syndrome. These findings identify digestive functions and conserved molecular mechanisms in LREs that are crucial for vertebrate growth and survival.

Presented by Jieun Esther Park