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Review
. 2022 Mar 16:13:799309.
doi: 10.3389/fimmu.2022.799309. eCollection 2022.

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

Jianxuan Sun  1   2 , Xingyu Zhong  1 , Xiaoyu Fu  1 , Heather Miller  3 , Pamela Lee  4 , Bing Yu  1 , Chaohong Liu  1
Affiliations
Review

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

Jianxuan Sun et al. Front Immunol. .

Abstract

Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.

Keywords: B cell; NK cell; T cell; WAS; actin regulators.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Domain structures of actin regulators important for lymphocytes. THY, thymosin β actin-binding motif; WH1, WASP Homology domain-1; B, Basic domain; GBD, GTPase binding domain; PP, poly-proline; WH2, WASP Homology domain-2; C, Connecting sequence; A, Acidic sequence; SHD, SCAR-homology domain; WAHD1, WASH Homology domain; TBR, Tubulin binding region; HD, Helical domain; DID, diaphanous autoregulatory domain; DD, dimerization domain; CC, coiled coil region; FH1, formin homology domain 1; FH2, formin homology domain 2; DAD, diaphanous autoregulatory domain; ADF, actin depolymerizing factor; U, unique region; CC, coiled-coil. (B) Conformation of Arp2/3 complex. ARP2; ARP3; and ARP complex-1~5 (ARPC1~5) are shown.
Figure 2
Figure 2
Different actin regulators play distinct roles in actin dynamics in lymphocytes. As actin-monomer-binding proteins, profilin and thymosin beta 4 (Tβ4) bind G-actin and prevent it from polymerizing, while formins act in an opposite manner, promoting actin filament polymerization. The activation of Arp2/3 complex requires NPFs including WAVE, JMY, WASp/N-WASp, WASH, and WAHMM, which is needed for branching F-actin. The severing of F-actin is mediated by cofilin. In the above process, actin undergoes dynamic changes in lymphocytes, thereby regulating cellular activity and function.
Figure 3
Figure 3
Formins’ role in regulating actin dynamics. The FH2 domain of formins close to the C-terminus can bind to the barbed end of filaments, while the FH1 domain near the N-terminus can bind to profilin-actin, thus increasing the concentration of actin monomers around filaments and positively promoting their polymerization.
Figure 4
Figure 4
N-WASP is involved in signaling pathways of T cells. (A) In CD4+ T cells, N-WASP is activated by CaM and enters the nucleus to coordinate the Arp2/3 complex to participate in the expression of cytokines. (B) In CD8+ T cells, N-WASP receives signals from NKG2D and participates in downstream cofilin dephosphorylation while also mediating the inhibition of cellular chemotaxis.
Figure 5
Figure 5
The Arp2/3 complex is involved in TCR signaling. Upon receiving signals from MHC molecules, TCR/CD3 can transmit stimuli to the Arp2/3 complex via tyrosine kinases such as Fyn, LCK, and ZAP-70. In this process, WASp family proteins play an important mediating role as direct activators of the Arp2/3 complex. The activated Arp2/3 complex has the ability to promote branched filament polymerization, which together with other T cell signaling-induced activation of actin regulators (e.g., cofilin and profilin) modulates the actin cytoskeleton, which is important for the biological activities of T cells, especially for IS formation.
Figure 6
Figure 6
Cofilin involves in T cell signaling. Several signaling pathways in T cells contain cofilin, including: (A) PLC-PIP2 pathway belonging to the TCR signaling, (B) protein phosphorylation belonging to co-stimulation signaling, and (C) protein oxidation. Activated cofilin can mediate actin entry into the nucleus and play a regulatory role in gene transcription. PP1/PP2A: protein serine/threonine phosphatases of type 1 and type 2A, ROS, reactive oxygen species.
Figure 7
Figure 7
Regulation of N-WASP and WASP in B cells. In B cells, N-WASP is inhibited by Btk, which in turn is negatively regulated by SHIP-1. The regulation of WASP depends on Btk for activation.
Figure 8
Figure 8
Cofilin in B cells. (A) Cofilin receives signals from the BCR. (B) Cofilin mediates the depolymerization of microfilaments on the membrane surface upon receiving TLR signaling, which increases BCR motility and facilitates the BCR signaling.
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