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Review
. 2013 Nov;256(1):48-62.
doi: 10.1111/imr.12102.

The actin-bundling protein L-plastin supports T-cell motility and activation

Sharon Celeste Morley  1
Affiliations
Review

The actin-bundling protein L-plastin supports T-cell motility and activation

Sharon Celeste Morley. Immunol Rev. 2013 Nov.

Abstract

Tight regulation of actin dynamics is essential for T-cell trafficking and activation. Recent studies in human and murine T cells reveal that T-cell motility and full T-cell activation require the hematopoietic-specific, actin-bundling protein L-plastin (LPL). T cells lacking LPL do not form fully mature synapses and thus demonstrate reduced cytokine production and proliferation. Reduction or loss of LPL expression also reduces the velocity of T cells and impairs thymic egress and intranodal motility. Whereas dispensable for proximal T-cell receptor and chemokine receptor signaling, LPL is critical to the later stages of synapse maturation and cellular polarization. Serine phosphorylation, calcium, and calmodulin binding regulate the bundling activity and localization of LPL following T-cell receptor and chemokine receptor engagement. However, the interaction between these regulatory domains and resulting changes in local control of actin cytoskeletal structures has not been fully elucidated. Circumstantial evidence suggests a function for LPL in either the formation or maintenance of integrin-associated adhesion structures. As LPL may be a target of the commonly used immunosuppressive agent dexamethasone, full elucidation of the regulation and function of LPL in T-cell biology may illuminate new pathways for clinically useful immunotherapeutics.

Keywords: L-plastin; T cells; actin cytoskeleton; immunological synapse; lamellipod; motility.

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Figures

Fig. 1
Fig. 1. Actin dynamics are critical to T-cell motility and activation
(A). Motile T cells assume a polarized shape, with a lamellipod at the leading edge and a uropod at the trailing edge. Two networks of f-actin create the lamellipod and the lamella, with greater stability of bundles and filaments in the lamella and more rapid turnover of branching chains in the lamellipod. Contractile elements, such as the motor protein myosin II b (MIIB), are concentrated in the uropod. Arrow represents direction of retrograde actin flow. (B). The immunological synapse has been described as a radially symmetrical lamella/lamellipod, with actin flow and regulatory molecules similar to those found in a migrating cell. The dSMAC is analogous to the lamellipod (LP), the pSMAC to the lamella (LM) and the cSMAC as an actin-depleted area where signaling is terminated. This conceptual framework provides an explanation for the segregation of cell surface receptors and signaling molecules observed in the synapse and for the critical role of f-actin in forming and maintaining the synapse. (C). Proposed model for force generation and forward motion during cell movement, drawn from Giannone et al. (58). Step 1. Retrograde actin polymerization in the lamellipod (yellow) extends the actin network until it connects with a site of adhesion anchored in the lamella. Step 2. Contractile force generated by myosin (MII) pulls the lamellipodial actin, generating tension. Step 3. Tension on f-actin bends the lamellipod, retracting the edge, and a new site of adhesion forms. Step 4. The tip of the lamellipodia f-actin breaks off. Step 5. The cycle restarts.
Fig. 2
Fig. 2. Structure and function of LPL
(A). LPL is a 66 kDa protein encompassing an N-terminal regulatory ‘headpiece’ followed by two ABDs. A serine residue at position 5 is heavily phosphorylated following external stimulation. Two EF-hand loops create a putative calcium-binding domain, and a calmodulin-binding domain (Cal) has been described. LPL contains 4 calponin homology (CH) domains, with each pair creating an ABD. (B). LPL intercalates between actin filaments as polymerization occurs, stabilizing and bundling f-actin. ATP binding by G-actin enables polymerization, which occurs more quickly at the barbed end. Slow hydrolysis of ATP to ADP results in depolymerization, more likely to occur at the pointed end. Diagrams are similar to those previously published (134).
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