Recruitment of dynein to the Jurkat immunological synapse

Combs, Jeffrey; Kim, Soo Jin; Tan, Sarah; Ligon, Lee A.; Holzbaur, Erika L.F.; Kuhn, Jeffrey R.; Poenie, Martin

doi:10.1073/pnas.0600914103

Cited by 181 publications

(217 citation statements)

References 28 publications

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“…A functional connection between kinesin, a microtubule plus-end directed motor, and JNK activity has been reported (24). Moreover, dynein has been shown to be involved in MTOC polarization (25). ERK2 and JNK1 signals may synergize to modulate the motor activities of kinesin and dynein molecules through phosphorylation, or they may work in parallel, each targeting some critical step during MTOC polarization.…”

Section: Discussionmentioning

confidence: 99%

Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity

Chen

Trivedi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

139

158

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Section: Discussionmentioning

confidence: 99%

Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity

Chen

Trivedi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

139

158

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“…NK cells are more easily trapped in long-lasting (>30 min) interactions, decreasing availability for sequential target cell interactions. Stable interface actin accumulation could impair killing by preventing repolarization toward secondary targets, as dynein motors associated with the peripheral actin ring are used to position the microtubule organizing center (MTOC) at the cytolytic effector/target cell interface (30). In addition, long lasting NK cell/target cell couples did not lead to target cell lysis, thus further diminishing killing at the population level.…”

Section: Discussionmentioning

confidence: 99%

Transience in polarization of cytolytic effectors is required for efficient killing and controlled by Cdc42

Sinai¹,

Nguyen²,

Schatzle³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cytolytic effectors polarize toward target cells for effective killing and IFN-γ secretion. The spatiotemporal features of this polarization and their importance for cytolysis have not been resolved. In cytotoxic T cells and natural killer (NK) cells, transient polarization was consistently associated with effective killing. Polarization was regulated by Cdc42, a small Rho family GTPase universally critical for cytoskeletal dynamics. Transient accumulation of active Cdc42 at the cytolytic effector/target cell interface and focus of such accumulation on the interface center were closely related to cytolysis. Surprisingly, however, the intensity of Cdc42 activation was not. We interfered with Cdc42 activation in NK cells such that sustained polarization in long lasting nonkilling cell couples was selectively blocked. Thus the proportion of the NK cell population displaying transient polarization was increased. As a consequence, cytolytic responder frequency and IFN-γ production were enhanced upon such interference with Cdc42 activation. These data support the notion that transience in polarization is critical for cytolytic effector function, likely by preventing cytolytic effectors from becoming trapped in nonproductive target cell interactions. Each can also secrete IFN-γ to modulate adaptive immune function. To acquire effector capability, cytolytic effectors need to be primed. CTL priming occurs as the consequence of naive CD8 T cell interactions with antigen-presenting dendritic cells. NK cell priming requires cytokines generated predominantly by dendritic cells. However, the nature of the cytokines involved is less certain. IL-12 and IL-18 enable NK cells to secrete IFN-γ (1, 2) and are synergistic (3). IL-15 can promote NK cell expansion (4, 5). IL-15 needs transpresentation by the IL-15 receptor α chain (6, 7), which is induced on dendritic cells by engagement of Toll-like receptors (7). High concentrations of IL-2 effectively prime NK cells in vitro, as often used in clinical settings (8, 9). However, in vivo, IL-2 is dispensable for NK cell priming (5). To understand the role of the polarization of cytolytic effector in their function, the effect of priming conditions on NK cell polarization needs to be taken into account.Target cell contact triggers the complex polarization of primed cytolytic effectors, recruitment of cytolytic granules to the interface (10, 11), cytoskeletal reorientation (12, 13), and receptor clustering (14,15). Cytolytic effector polarization is likely functionally important, as key regulators of cytoskeletal dynamics, Vav and WASP, play critical roles (16-19). However, WASP and Vav are complex molecules with functions that may or may not require cytoskeletal regulation (20,21). The Rho family GTPases Rac and Cdc42 are the central regulators of cytoskeletal dynamics in many cell types (22). Although it has been established that Rac is required for cell coupling and polarization of cytolytic granules (16), the role Cdc42 has not been addressed. Despite the established importance of ...

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“…While diffusion could mediate this effect (e.g., in the context of a binding-protein gradient), the finding suggested that stimulated NF-B might use active transport. Brain NF-B has been reported to coimmunoprecipitate dynein intermediate chain and components of dynactin in the presence of cross-linkers (10), and dynein is also concentrated at the postsynaptic density in neurons (23) and recruited to the immunological synapse in T cells (24), both sites which can signal NF-B activation. We have now shown that NF-B nuclear transport following stimulation depends upon the dynein molecular motor.…”

Section: Discussionmentioning

confidence: 99%

Stimulated nuclear translocation of NF-κB and shuttling differentially depend on dynein and the dynactin complex

Shrum¹,

DeFrancisco

Meffert

2009

Proc. Natl. Acad. Sci. U.S.A.

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Translocation from the cytoplasm to the nucleus is required for the regulation of gene expression by transcription factors of the nuclear factor kappa B (NF-B) family. The p65:p50 NF-B heterodimer that predominates in many cell types can undergo stimulated movement, following degradation of the I B inhibitor, as well as shuttling in the absence of stimulation with I B bound. Disruption of the dynactin complex and knockdown of endogenous dynein were used to investigate the nuclear translocation requirements for stimulated and shuttling movement of NF-B. A differential dependence of these two modes of transport on the dynein molecular motor and dynactin was found. NF-B used active dynein-dependent transport following stimulation while translocation during shuttling was mediated by a dynein-independent pathway that could be potentiated by dynactin disruption, consistent with a process of facilitated diffusion. Nuclear translocation and activation of NF-B-dependent gene expression showed a dependence on endogenous dynein in a variety of cell types and in response to diverse activating stimuli, suggesting that dyneindependent transport of NF-B may be a conserved mechanism in the NF-B activation pathway and could represent a potential point of regulation.NF-kappaB ͉ nuclear transport ͉ transcription ͉ molecular motor ͉ active transport T he NF-B or Rel transcription factors are ubiquitouslyexpressed regulators of gene expression that are essential for physiological processes ranging from innate and adaptive immunity to learning and memory. NF-B functions as a dimer and is retained in a latent form in the cytoplasm, bound to the inhibitor of NF-B (I B). In the canonical pathway, incoming stimuli trigger activation of the I B-kinase complex (IKK) that phosphorylates I B␣ and leads to its degradation. The subsequent translocation of active I B-free NF-B from cytoplasm to nucleus is critical for NF-B-dependent gene expression. In the absence of I B degradation, NF-B can undergo stimulusindependent movement back and forth between the nucleus and cytoplasm in a process termed shuttling (1). Shuttling of p65:p50 NF-B dimers is believed to result from incomplete masking of the p50 nuclear localization sequence (NLS) by bound I B␣ and can be observed by blocking exportin1/crm1-mediated nuclear export under unstimulated conditions (2).While NF-B requires importin family members to cross the nuclear pore (3), the molecular mechanisms underlying NF-B cytoplasmic movement remain poorly understood. Studies examining the role of microtubules are conflicting, possibly because the pharmacological agents that disrupt microtubules result in a confounding activation of NF-B (4-10). Microtubule-dependent transport can also be probed by disrupting the multisubunit dynactin complex, and it was recently reported that dynactin could play a role in the nuclear accumulation of neuronal NF-B (10). Dynactin regulates the processivity of molecular motors using microtubules, including cytoplasmic dynein and kinesin (11,12). Dynein is a retrograde m...

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Recruitment of dynein to the Jurkat immunological synapse

Cited by 181 publications

References 28 publications

Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity

Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity

Transience in polarization of cytolytic effectors is required for efficient killing and controlled by Cdc42

Stimulated nuclear translocation of NF-κB and shuttling differentially depend on dynein and the dynactin complex

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