MARCH1 protects the lipid raft and tetraspanin web from MHCII proteotoxicity in dendritic cells

Jaehak Oh; Justin S A Perry; Heather Pua; Nicole Irgens-Möller; Satoshi Ishido; Chyi-Song Hsieh; Jeoung-Sook Shin

doi:10.1083/jcb.201611141

MARCH1 protects the lipid raft and tetraspanin web from MHCII proteotoxicity in dendritic cells

J Cell Biol. 2018 Apr 2;217(4):1395-1410. doi: 10.1083/jcb.201611141. Epub 2018 Jan 25.

Authors

Jaehak Oh^{1

2}, Justin S A Perry³, Heather Pua^{2

3}, Nicole Irgens-Möller^{1

2}, Satoshi Ishido⁴, Chyi-Song Hsieh⁵, Jeoung-Sook Shin^{6

2}

Affiliations

¹ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA.
² Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA.
³ Department of Pathology, University of California, San Francisco, San Francisco, CA.
⁴ Department of Microbiology, Hyogo College of Medicine 1-1, Mukogawa-cho, Nishinomiya, Japan.
⁵ Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO.
⁶ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA [email protected].

Abstract

Dendritic cells (DCs) produce major histocompatibility complex II (MHCII) in large amounts to function as professional antigen presenting cells. Paradoxically, DCs also ubiquitinate and degrade MHCII in a constitutive manner. Mice deficient in the MHCII-ubiquitinating enzyme membrane-anchored RING-CH1, or the ubiquitin-acceptor lysine of MHCII, exhibit a substantial reduction in the number of regulatory T (Treg) cells, but the underlying mechanism was unclear. Here we report that ubiquitin-dependent MHCII turnover is critical to maintain homeostasis of lipid rafts and the tetraspanin web in DCs. Lack of MHCII ubiquitination results in the accumulation of excessive quantities of MHCII in the plasma membrane, and the resulting disruption to lipid rafts and the tetraspanin web leads to significant impairment in the ability of DCs to engage and activate thymocytes for Treg cell differentiation. Thus, ubiquitin-dependent MHCII turnover represents a novel quality-control mechanism by which DCs maintain homeostasis of membrane domains that support DC's Treg cell-selecting function.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Animals
Cell Communication*
Cell Differentiation
Cells, Cultured
Coculture Techniques
Dendritic Cells / enzymology*
Dendritic Cells / immunology
Dendritic Cells / pathology
Histocompatibility Antigens Class II / genetics
Histocompatibility Antigens Class II / immunology
Histocompatibility Antigens Class II / metabolism*
Homeostasis
Lymphocyte Activation
Membrane Microdomains / enzymology*
Membrane Microdomains / immunology
Membrane Microdomains / pathology
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism
Signal Transduction
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism*
T-Lymphocytes, Regulatory / transplantation
Tetraspanins / immunology
Tetraspanins / metabolism*
Thymocytes / immunology
Thymocytes / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / immunology
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

Histocompatibility Antigens Class II
Receptors, Antigen, T-Cell
Tetraspanins
MARCH1 protein, mouse
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding