MARCH proteins are membrane-associated Ring-CH E3 ubiquitin ligases that ubiquitinate and regulate cell surface expression of major histocompatibility complexes I and II as well as T- and B-cell co-activation receptors, to dampen immune responses.
Having previously shown that MARCH2,3,4 and 9 also down regulate cell surface expression of the receptor for interleukin-6 (IL6Rα), Sandow et al perform an unbiased cell surface specific proteomic analysis to determine other potential cell surface targets of these four proteins.
Using IonOpticks Aurora Series columns coupled online to a Q-Exactive mass spectrometer (Thermo Fisher), the authors identify many new cell surface protein targets, adding immune cell adhesion and migration to the growing list of immune functions modulated by MARCH protein expression.
The abundance of some is regulated by a single MARCH, many others by two or more. As such, Integrin α4β1 (VLA4 or VCAM-1 receptor) is downregulated only by MARCH2. A physiological role for this was confirmed in MARCH2 knockout mice, where Integrin α4 is upregulated specifically in mature B-cells found in the bone marrow, accompanied by decreased numbers of B-cells in the spleen. It appears MARCH2 down regulates integrin α4 expression on B cells as they mature in the bone marrow. This facilitates their release from the bone marrow microenvironment to traffic to the spleen, while other hemopoietic cells remain unaffected.
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Proteomic analyses reveal that immune integrins are major targets for regulation by Membrane-Associated Ring-CH (MARCH) proteins MARCH2, 3, 4 and 9.
Proteomics, 21, e2000244. 11 June 2021. doi: https://doi.org/10.1002/pmic.202000244
Jarrod J. Sandow, Andrew I. Webb, Dina Stockwell, Nadia J. Kershaw, Cyrus Tan, Satoshi Ishido, Warren S. Alexander, Douglas J. Hilton, Jeffrey J. Babon and Nicos A. Nicola
Commentary by Jarrod Sandow, PhD.
About the author
Jarrod has a background in biotechnology and completed his PhD at the Institute of Medical and Veterinary Science in Adelaide. He is a co-inventor of IonOpticks’ core technology and is driven towards developing innovative solutions for the global proteomics research community that will enable scientists and clinicians to discover more from their samples to accelerate advances in biological and medical research.