Life science
Medical care, Drug development

Elucidation of molecular mechanisms of immune cell
migration and their application to medicine
Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine
Assistant Professor Hyota Takamatsu

https://researchmap.jp/thyota

Professor Atsushi Kumanogoh

https://researchmap.jp/read0051725

Life science

Abstract
Immune cells use the actin and myosin-mediated cellular contractility (actomyosin contraction) to move through confined spaces in vivo, but the detailed regulatory mechanisms are unknown.
When Lamtor1, a component of the lysosomal membrane-tetheredRagulator complex was specifically deleted in immune cells, theinduction of the acquired immune system was impaired due tothe impaired migration of dendritic cells. In the confined space,dendritic cells were unable to move forward due to impaired contraction in the rear of cell. Furthermore, the Ragulator complex regulates actomyosin contraction by altering the localization of MLCP
through interacting with MPRIP, which anchors myosin light chain
phosphatase (MLCP) to actin.

▍ Background & Results▍ Significance of the research and Future perspective
This study revealed that when chemokine signaling induces anterior-posterior cell polarity, lysosomes localize to the posterior ofthe cell, and the Ragulator complex on the lysosomal membraneassociates with MPRIP to inhibit the binding of MPRIP with MYPT1,
which divert MLCP, from the actomyosin contractile site. Since
mutations in Ragulator complex components are known to cause
human immunodeficiency diseases and cancer cells also utilize
actomyosin contraction during cancer metastasis, the interaction
between the Ragulator complex and MPRIP may provide a new
therapeutic target against human diseases such as an inflammation, autoimmune diseases, anti-tumor immune responses, andcancer metastasis caused by cell migration.

Immune cells migrate throughout the body to monitor invading
pathogens. Among immune cells, dendritic cells are highly motile
and are responsible for capturing invading pathogens, migrating
to lymph nodes and spleen, and presenting antigens to lymphocytes, resulting in inducing antigen-specific immune responses
to protect the host from pathogens. Dendritic cells migrate in an
elongation-contraction pattern in response to chemokines, in which
the anterior region of the cell elongates and the posterior region
contracts by actomyosin contraction. However, the regulatory
mechanism of actomyosin contraction is unknown. It has beenreported that the Ragulator complex, which anchors mTORC1 on
the lysosomal membrane for metabolism, is involved in cell motility,
but the mechanism of its involvement in actomyosin contraction isunknown.
We generated mice lacking dendritic cell-specific Lamtor1, acomponent of the Ragulator complex, and examined the functionof Lamtor1 in dendritic cells and found that Lamtor1 is involved inactomyosin contraction. Dendritic cell-specific Lamtor1-deficient
mice had a reduced number of dendritic cells migrating from peripheral tissues to lymph nodes and a markedly reduced inductionof the acquired immune system. Furthermore, observation of dendritic cell migration in an experimental system that recapitulated
dendritic cell migration in vivo revealed that Lamtor1-deficient
dendritic cells were unable to advance due to impaired actomyosin contraction in the posterior region of the cell. Investigating themechanism of this defect, we found that the Ragulator complex interacts with actin-anchored MPRIP (myosin phosphatase Rho-interacting protein), which leads to competitively interfere the binding
between MPRIP and MYPT1, a component of myosin light chain
phosphatase complex (MLCP), a brake on actomyosin contraction.
The sequestration of MLCP from actin leads to the phosphorylationof MLC, promoting the actomyosin contraction. In this study, we
elucidated the detailed mechanism of immune cell migration, bywhich the Ragulator complex regulates actomyosin contraction
through its interaction with MPRIP.

Figure 1

Figure 2
P a t e n t
Tr e a t i s e

Nakatani, Takeshi; Tsujimoto, Kohei; Park JeongHoon; et al. The lysosomal Ragulator complex plays an essential role in leukocyte trafficking by activating
myosin II. Nature Communications. 2021, 12(1): 3333, doi: 10.1038/s41467-021-23654-3

URL
K e y w o r d immune cell migration, actomyosin contraction, the ragulator complex, lamtor1, MPRIP