Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A

Abstract

Significance Natural killer (NK) cells are cytolytic effector cells of the innate immune system. They are critical for the control of viral infection and malignancy, and patients with impaired NK cell function have recurrent and often fatal viral infection and malignancy. NK cell cytotoxic function is exerted by secretion of specialized lytic granules. Here, we show that deconstruction of synaptic cortical filamentous (F)-actin by Coronin 1A (Coro1A) is required for NK cell cytotoxicity through the remodeling of F-actin to enable lytic granule secretion. We define this requirement for remodeling using superresolution nanoscopy and Coro1A-deficient NK cells. In addition, we use NK cells from a patient with a rare Coro1A mutation, thus illustrating a critical link between Coro1A function and human health.

Molecular Control of B Cell Activation and Immunological Synapse Formation

“…However, the samples are subjected to strong lasers often leading to some compromises in the imaging conditions. STED microscopy has been used to image the rearrangements of the actin cytoskeleton in natural killer cell immunological synapse (56), and to demonstrate that TCR microclusters are composed of several smaller clusters (54). FRET is a powerful method for protein-protein interaction studies in living cells.…”

Regulation of immune cell homeostasis and function by coronin 1

“…Also, in one case, coronin 1 deficiency was found to be associated with reduced NK cell numbers and cytolytic function that were reported to be linked to defective actin deconstruction [45]. Whether or not the reported variations in B cell and natural killer (NK) cell numbers and/or functions are related to the associated genetic aberrations in these patients [39,44,45] rather than coronin 1 deficiency per se, remains to be analyzed.…”

“…Also, in one case, coronin 1 deficiency was found to be associated with reduced NK cell numbers and cytolytic function that were reported to be linked to defective actin deconstruction [45]. Whether or not the reported variations in B cell and natural killer (NK) cell numbers and/or functions are related to the associated genetic aberrations in these patients [39,44,45] rather than coronin 1 deficiency per se, remains to be analyzed. Importantly, the single patient analyzed to date with an exclusive coronin 1 deletion in the absence of other genetic aberrations [6,38], shows a normal phenotype with respect to B/NK cell numbers and functionality, although it cannot be excluded that the minimal residual coronin 1 expression may restore some coronin 1 function in this patient.…”

“…At the level of immune cell composition, however, all the patients irrespective of associated genetic aberrations, showed profound naïve T cell lymphopenia, characterized by drastically reduced CD3 + CD4 + CD45RA + and CD3 + CD8 + CD45RA + cells with relatively minor alterations of B cell and NK cell numbers or their function [6,38,39,44,45]. Also, in one case, coronin 1 deficiency was found to be associated with reduced NK cell numbers and cytolytic function that were reported to be linked to defective actin deconstruction [45].…”

Molecular mechanisms and functional implications of polarized actin remodeling at the T cell immunological synapse

“…Recent work has implicated coronin1 in this localized F-actin effacement. NK cells lacking coronin1 exhibit enhanced levels of synaptic F-actin, accompanied by defects in degranulation and killing[134]. Interestingly, loss of coronin1 in this context does not appear to cause any defects in activation-induced signaling, unlike what has been observed for T cells.…”