KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation

Craig R Brooks; Melissa Y Yeung; Yang S Brooks; Hui Chen; Takaharu Ichimura; Joel M Henderson; Joseph V Bonventre

doi:10.15252/embj.201489838

KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation

EMBO J. 2015 Oct 1;34(19):2441-64. doi: 10.15252/embj.201489838. Epub 2015 Aug 17.

Authors

Craig R Brooks¹, Melissa Y Yeung², Yang S Brooks³, Hui Chen⁴, Takaharu Ichimura⁵, Joel M Henderson⁴, Joseph V Bonventre⁶

Affiliations

¹ Department of Medicine, Renal Division, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA [email protected] [email protected].
² Department of Medicine, Renal Division, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA Transplantation Research Center, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA.
³ Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA Department of Dermatology, Harvard Medical School, Boston, MA, USA.
⁴ Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
⁵ Department of Medicine, Renal Division, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA.
⁶ Department of Medicine, Renal Division, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA Harvard Stem Cell Institute, Cambridge, MA, USA [email protected] [email protected].

Abstract

Phagocytosis of apoptotic cells by both professional and semi-professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM-1/TIM-1 is a phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM-1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC3 in multi-membrane organelles. KIM-1-mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM-1-mediated phagocytosis leads to pro-tolerogenic antigen presentation, which suppresses CD4 T-cell proliferation and increases the percentage of regulatory T cells in an autophagy gene-dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response.

Keywords: MHC; T regs; acute kidney injury; biomarker; heterophagy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antigen Presentation / physiology*
Apoptosis
Autophagy-Related Protein 5
Autophagy-Related Protein-1 Homolog
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology*
Cell Proliferation / physiology
HEK293 Cells
Hepatitis A Virus Cellular Receptor 1
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / immunology*
Lipoylation / physiology
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology*
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / immunology*
Phagocytosis / physiology*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / immunology*
Reactive Oxygen Species / immunology
Receptors, Virus / genetics
Receptors, Virus / immunology*

Substances

ATG5 protein, human
Autophagy-Related Protein 5
HAVCR1 protein, human
Hepatitis A Virus Cellular Receptor 1
Intracellular Signaling Peptides and Proteins
MAP1LC3A protein, human
Membrane Glycoproteins
Microtubule-Associated Proteins
Reactive Oxygen Species
Receptors, Virus
Autophagy-Related Protein-1 Homolog
Protein Serine-Threonine Kinases
ULK1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding