The Cytoskeletal Motor Protein Myosin IIA Tunes the NK cell Activation Threshold

We recently demonstrated that the dynamics of the F-actin network play a crucial role in the regulation of SHP-1 enzymatic activity by affecting its conformational structure. Blocking actin dynamics at the inhibitory NK cell immunological synapse (NKIS) results in reduced SHP-1 activity, increased cytolytic granule secretion, and suppressed tumor growth in Non-Hodgkin Lymphma (NHL)-bearing mice in-vivo. Our findings revealed that actin retrograde flow is essential for determining the activation threshold and the functional outcome of NK cells (Matalon et al. EMBO, 37:e96264, 2018). In the present work, we demonstrate for the first time that Myosin IIA plays also a role in the modulation of NK cell signaling cascade by regulating SHP-1 conformational state and its activity. Inhibition of Myosin IIA motor function leads to an accumulation of the inactive closed conformation of SHP-1 at the NKIS, leading to high phosphorylation of the SHP-1 substrates VAV1 and PLCg-1/2, and to an increase in NK cell activation.

Hence, understanding the mechanisms that regulate SHP-1 activity may lead to the development of novel immuno-therapeutic strategies for the treatment of cancer, viral infections, and autoimmunity that are caused by abnormal immune cell activity.