Emerging functions of cytoskeletal proteins in immune diseases

Abstract

Immune cells are especially dependent on the proper functioning of the actin cytoskeleton, and both innate and adaptive responses rely on it. Leukocytes need to adhere not only to substrates but also to cells in order to form synapses that pass on instructions or kill infected cells. Neutrophils literally squeeze their cell body during blood extravasation and efficiently migrate to the inflammatory focus. Moreover, the development of immune cells requires the remodeling of their cytoskeleton as it depends on, among other processes, adhesive contacts and migration. In recent years, the number of reports describing cytoskeletal defects that compromise the immune system has increased immensely. Furthermore, a new emerging paradigm points toward a role for the cellular actin content as an essential component of the so-called homeostasis-altering molecular processes that induce the activation of innate immune signaling pathways. Here, we review the role of critical actin-cytoskeleton-remodeling proteins, including the Arp2/3 complex, cofilin, coronin and WD40-repeat containing protein 1 (WDR1), in immune pathophysiology, with a special focus on autoimmune and autoinflammatory traits.

The Actin Cytoskeleton Responds to Inflammatory Cues and Alters Macrophage Activation

“…All of these points argue that dysregulated Arp2/3–myosin balance in innate immune cells may have significant impacts on adaptive immune function. Wiskott–Aldrich syndrome, Arpc1b deficiency, Hem1 deficiency and numerous other human actinopathies present with elements of autoinflammation and immunodeficiency [ 32 , 76 ]. Many more cell types than macrophages are impacted by these syndromes, including platelets, neutrophils, T cells and B cells [ 32 , 76 , 77 ].…”

“…Wiskott–Aldrich syndrome, Arpc1b deficiency, Hem1 deficiency and numerous other human actinopathies present with elements of autoinflammation and immunodeficiency [ 32 , 76 ]. Many more cell types than macrophages are impacted by these syndromes, including platelets, neutrophils, T cells and B cells [ 32 , 76 , 77 ]. Nonetheless, the current study indicates that dysregulation of the actomyosin cytoskeleton may contribute to disease by impairing coordination between the innate and adaptive immune response.…”

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

“…As viruses usurp host ribosomes to replicate, cognition is likely affected, probably explaining the lethargy of “sickness behavior” observed during viral infection ( Li, 2019 ). Moreover, cytoskeletal proteins were recently linked to inflammation and immunogenicity, suggesting that viruses can induce both immunosuppression and immune activation via cytoskeletal manipulation ( Moulding et al., 2013 ; Mostowy and Shenoy, 2015 ; Tur-Gracia and Martinez-Quiles, 2021 ). Along these lines, maternal immunological tolerance of the fetus vs. inflammation and preeclampsia may be determined by the viral hijacking of cytoskeleton ( Harmon et al., 2016 ; Wang et al., 2019 ).…”

The Actin Regulators Involved in the Function and Related Diseases of Lymphocytes

“…The binding of coronin with actin enhances the binding of cofilin to actin as the filament twist is changed. Additionally, the cooperation between coronin and slingshot-1L increases the activity of cofilin ( 106 , 179 ). In yeast, coronins bind Arp2/3 directly by a coiled-coil domain and suppress the nucleating activity of Arp2/3 ( 107 ).…”

“…In combination with other findings ( 198 , 383 ), this mutation impairs the regulation of actin by WDR1, leading to increased levels of F-actin, which induces an IL-18-mediated inflammatory response downstream. Thus, WDR1 is extremely important for neutrophil function and its deficiency can lead to auto-inflammation and immunodeficiency ( 179 ).…”