Invited
Speaker
Identification of Translational Factors Involved in the Control
of Inflammation and Immunity: Implications for Novel Therapeutic Potential
Sunghoon Kim
Korea
Aminoacyl-tRNA synthetases (ARSs) are ancient enzymes essential for
protein synthesis and cell viability. However, accumulating evidences
demonstrate that these enzymes form a complex protein network with
each other and with various cellular factors to coordinate translation
process and diverse signal pathways (1). Among ARSs and their interacting
factors (AIMPs), several components were shown to control inflammation
and immune responses. In particular, lysyl-tRNA synthetase (KRS) serves
as a key regulator of inflammation and immune response with unique
working mechanisms. It is secreted from the cells as cytokine upon
the stimulus of TNF-alpha and triggers inflammatory response (2).
More surprisingly, KRS is also translocated into nucleus to control
gene expression via its second catalytic activity (3). AIMP1/p43 is
a factor associated with KRS within a macromolecular ARS complex (4).
This factor also plays a dual role in the regulation of inflammation
and immunity. In extracellular space, it works as cytokine activating
immune responses that can be used as an immunotherapy against cancer.
This possibility was confirmed by the fact that tumor growth was severely
suppressed by systemic administration of purified AIMP1 in stomach
cancer xenograft model. Interestingly, AIMP1 knockout mice display
severe autoimmune phenotypes similar to lupus. Investigation of molecular
etiology for this symptom revealed that AIMP1 prevents ER-resident
chaperone, gp96 from extracellular exposure that may result in the
activation of immune system. Some chemicals interfering AIMP1 and
gp96 interaction have been screened. These chemicals showed expected
activity in vitro and in vivo as immune suppressant. Thus, many components
involved in translation appear to play critical roles in the control
of immune system and provide novel therapeutic points to explore novel
immune-controlling drugs.
References
- Park et al. Proc. Natl. Acad. Sci. USA, 105:11043-11049, 2008
- Park et al. Proc. Natl. Acad. Sci. USA, 102:6356-6361, 2005
- Yannay-Cohen et al. Mol. Cell, 34:603-611, 2009
- Lee et al. Exp. Opinion Drug Discovery, 3:945-957, 2008
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