TAGLN2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse

Na, Bo-Ra; Kim, Hye‐Ran; Piragyte, Indre; Oh, Hyun-Mee; Kwon, Min‐Sung; Akber, Uroos; Lee, Hyun Su; Park, Do‐Sim; Song, Woo Keun; Park, Chul–Seung; Im, Sungbin; Rho, Mun‐Chual; Hyun, Young Youl; Kim, Min‐Soo; Jun, Chang‐Duk

doi:10.1083/jcb.201407130

Cited by 75 publications

(121 citation statements)

References 42 publications

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“…17 In the present study, we also found that TAGLN2 was physically associated with LFA-1 through its CH domain, regardless of stimulation (Figure 1(d,e)), and corresponded to the activation of Rap1 (Figure 1(f)), which functions as a key regulator of LFA-1-dependent adhesion and migration of T cells. 18–20 These results suggested that TAGLN2, in addition to its biochemical characteristics enabling it to control actin dynamics, acted as a cytosolic factor to modulate ‘inside-out’ signaling of the integrin LFA-1.…”

Section: Resultssupporting

confidence: 75%

“…16 Among three TAGLN superfamily members, we recently reported that TAGLN2 is predominantly expressed in T cells and stabilizes cortical F-actin to maintain the IS. 17 We also found that TAGLN2 overexpression caused LFA-1 activation after TCR stimulation. 17 In the present study, we found that TAGLN2 physically associated with LFA-1 via its calponin homology (CH) domain and enhanced the activity of Rap1, a small GTPase that has been shown to regulate LFA-1 affinity and clustering.…”

Section: Introductionmentioning

confidence: 51%

“…17 We also found that TAGLN2 overexpression caused LFA-1 activation after TCR stimulation. 17 In the present study, we found that TAGLN2 physically associated with LFA-1 via its calponin homology (CH) domain and enhanced the activity of Rap1, a small GTPase that has been shown to regulate LFA-1 affinity and clustering. 18–20 This biochemical property of TAGLN2 may have several advantages when applied to cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 51%

“…From this perspective, we utilized TAGLN2 as we found in a previous report that TAGLN2 increases F-actin contents through stabilization of F-actin in T cells during IS formation. 17 Recently, we also found that TAGLN2 is significantly upregulated in macrophages in response to lipopolysaccharide and enhances macrophage phagocytic function, 26 demonstrating that TAGLN2 plays an essential role in actin dynamics at the immunological or phagocytic synapses. In the present study, more strikingly, drastic down-regulation of TAGLN2 in T cells from severe E0771 tumor-bearing mice further emphasizes that TAGLN2 is an important actin regulator for cytotoxic T cell adhesion to tumor target cells.…”

Section: Discussionmentioning

confidence: 93%

“…The schematic diagram in Supplemental Figure 1 indicates the potential mechanisms of action of TAGLN2 in T cells. TAGLN2 not only stabilized F-actin but also blocked cofilin-mediated actin polymerization, resulting in increased F-actin contents at the IS 17 and leading to prolonged T-cell activation and IL-2 production. Additionally, TAGLN2 regulated ‘inside-out’ integrin LFA-1 function when T cells received a primary antigen signal through the TCR, even though the ‘outside-in’ costimulatory signals were weak in the tumor microenvironment.…”

Section: Resultsmentioning

confidence: 99%

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Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

et al. 2018

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Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an ‘inside-out’ activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells. Notably, recombinant TAGLN2 fused with the protein transduction domain (TG2P) overcame the disadvantages of viral gene delivery, leading to a significant reduction in tumor growth in mice. TG2P also potentiated the CD19-targeted, chimeric antigen receptor (CAR)-modified T cells to kill Raji B-lymphoma cells. Our findings indicate that activating the TAGLN2–actin–LFA-1 axis is an effective strategy to potentiate the adoptive T-cell immunotherapy.

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Section: Resultssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

et al. 2018

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Glucose‐mediated mitochondrial reprogramming by cholesterol export at TM4SF5‐enriched mitochondria‐lysosome contact sites

Kim,

Park,

Kwak

et al. 2023

Cancer Communications

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BackgroundTransmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.MethodsHere, we explored the metabolic significance of TM4SF5 localization at mitochondria‐lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc.ResultsUpon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506‐binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho‐dynamic‐related protein I (DRP1) and certain mitophagy receptors at TM4SF5‐enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and β‐oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy.ConclusionsOur findings suggested that TM4SF5‐enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.

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Diversification of the calponin family proteins by gene amplification and repeat expansion of calponin‐like motifs

Ono

2021

Cytoskeleton

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The calponin family proteins in vertebrates, including calponin and transgelin (also known as SM22 or NP25), regulate actin-myosin interaction and actin filament stability and are involved in regulation of muscle contractility and cell migration. Related proteins are also present in invertebrates and fungi. Animals have multiple genes encoding calponin family proteins with variable molecular features, which are often expressed in the same tissues or cells. However, functional studies of this class of proteins have been reported only in limited species. Through database searches, I found that the calponin family proteins were diversified in animals by gene amplification and repeat expansion of calponin-like (CLIK) motifs, which function as actinbinding sequences. Transgelin-like proteins with a single CLIK motif are the most primitive type and present in fungi and animals. In many animals, additional calponin family proteins containing multiple CLIK motifs, as represented by vertebrate calponins with three CLIK motifs, are present. Interestingly, in several invertebrate species, there are uncharacterized calponin-related proteins with highly expanded repeats of CLIK motifs (up to 23 repeats in mollusks). These variable molecular features of the calponin family proteins may be results of evolutionary adaptation to a broad range of cell biological events.

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TAGLN2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse

Abstract: TAGLN2 stabilizes cortical F-actin and thereby maintains F-actin contents at the immunological synapse, which allows T cell activation following T cell receptor stimulation.

Cited by 75 publications

References 42 publications

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

Glucose‐mediated mitochondrial reprogramming by cholesterol export at TM4SF5‐enriched mitochondria‐lysosome contact sites

Diversification of the calponin family proteins by gene amplification and repeat expansion of calponin‐like motifs

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