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The involvement of β-actin in the signaling of transmembrane TNF-α-mediated cytotoxicity.
J Leukoc Biol. 2011 Jun; 89(6):917-26.JL

Abstract

Actin cytoskeleton has been shown to play a regulating role in several signaling pathways, and disruption of actin filament has been reported to increase sTNF-α-induced cell death. However, whether actin is involved in tmTNF-α-mediated cytotoxicity remains unclear. Here, we demonstrated that pretreatment of HL-60 with CytD or LatA to depolymerize actin significantly suppressed tmTNF-α-mediated apoptosis. Interestingly, tmTNF-α increased the actin immunoprecipitated by anti-TNFR2 but not anti-TNFR1 antibody, and disruption of the actin filament totally blocked this effect. In addition, TNFR1 knockdown by siRNA did not affect tmTNF-α-mediated cytotoxicity and the inhibitory effect of CytD, suggesting that the involvement of actin in the tmTNF-α-induced apoptosis is linked to the TNFR2 pathway. Our results revealed further that tmTNF-α signaled the inhibition of IκB degradation and NF-κB activity by recruiting RIP1 to and uncoupling TRAF2 from the TNFR2 complex. Nevertheless, CytD totally reversed the tmTNF-α signaling and activated NF-κB by recruiting TRAF2 to and dissociating RIP1 from the TNFR2 complex. Furthermore, tmTNF-α led to activation of caspase-8 by dissociation of cFLIP from TNFR2 and inhibition of the cFLIP expression. Activated caspase-8 cleft RIP1 to suppress NF-κB activity and also mediated tmTNF-α-induced apoptosis. However, CytD blocked the tmTNF-α-induced uncoupling of cFLIP from TNFR2 and prevented caspase-8 activation and the resulting cleavage of RIP1, converting the signaling for tmTNF-α-mediated apoptosis into one for activating NF-κB to survive. These results suggest that the actin cytoskeleton functions in transmitting signals via TNFR2 to mediate tmTNF-α-induced apoptosis.

Authors+Show Affiliations

Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21402772

Citation

Chen, Hui, et al. "The Involvement of Β-actin in the Signaling of Transmembrane TNF-α-mediated Cytotoxicity." Journal of Leukocyte Biology, vol. 89, no. 6, 2011, pp. 917-26.
Chen H, Xiao L, Zhang H, et al. The involvement of β-actin in the signaling of transmembrane TNF-α-mediated cytotoxicity. J Leukoc Biol. 2011;89(6):917-26.
Chen, H., Xiao, L., Zhang, H., Liu, N., Liu, T., Liu, L., Hu, X., Yan, D., Yang, K., Yin, B., Wang, J., Li, Q., & Li, Z. (2011). The involvement of β-actin in the signaling of transmembrane TNF-α-mediated cytotoxicity. Journal of Leukocyte Biology, 89(6), 917-26. https://doi.org/10.1189/jlb.1209812
Chen H, et al. The Involvement of Β-actin in the Signaling of Transmembrane TNF-α-mediated Cytotoxicity. J Leukoc Biol. 2011;89(6):917-26. PubMed PMID: 21402772.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The involvement of β-actin in the signaling of transmembrane TNF-α-mediated cytotoxicity. AU - Chen,Hui, AU - Xiao,Li, AU - Zhang,Hailong, AU - Liu,Na, AU - Liu,Tao, AU - Liu,Lili, AU - Hu,Xin, AU - Yan,Dan, AU - Yang,Kun, AU - Yin,Bingjiao, AU - Wang,Jing, AU - Li,Qingfen, AU - Li,Zhuoya, Y1 - 2011/03/14/ PY - 2011/3/16/entrez PY - 2011/3/16/pubmed PY - 2011/9/16/medline SP - 917 EP - 26 JF - Journal of leukocyte biology JO - J Leukoc Biol VL - 89 IS - 6 N2 - Actin cytoskeleton has been shown to play a regulating role in several signaling pathways, and disruption of actin filament has been reported to increase sTNF-α-induced cell death. However, whether actin is involved in tmTNF-α-mediated cytotoxicity remains unclear. Here, we demonstrated that pretreatment of HL-60 with CytD or LatA to depolymerize actin significantly suppressed tmTNF-α-mediated apoptosis. Interestingly, tmTNF-α increased the actin immunoprecipitated by anti-TNFR2 but not anti-TNFR1 antibody, and disruption of the actin filament totally blocked this effect. In addition, TNFR1 knockdown by siRNA did not affect tmTNF-α-mediated cytotoxicity and the inhibitory effect of CytD, suggesting that the involvement of actin in the tmTNF-α-induced apoptosis is linked to the TNFR2 pathway. Our results revealed further that tmTNF-α signaled the inhibition of IκB degradation and NF-κB activity by recruiting RIP1 to and uncoupling TRAF2 from the TNFR2 complex. Nevertheless, CytD totally reversed the tmTNF-α signaling and activated NF-κB by recruiting TRAF2 to and dissociating RIP1 from the TNFR2 complex. Furthermore, tmTNF-α led to activation of caspase-8 by dissociation of cFLIP from TNFR2 and inhibition of the cFLIP expression. Activated caspase-8 cleft RIP1 to suppress NF-κB activity and also mediated tmTNF-α-induced apoptosis. However, CytD blocked the tmTNF-α-induced uncoupling of cFLIP from TNFR2 and prevented caspase-8 activation and the resulting cleavage of RIP1, converting the signaling for tmTNF-α-mediated apoptosis into one for activating NF-κB to survive. These results suggest that the actin cytoskeleton functions in transmitting signals via TNFR2 to mediate tmTNF-α-induced apoptosis. SN - 1938-3673 UR - https://www.unboundmedicine.com/medline/citation/21402772/The_involvement_of_β_actin_in_the_signaling_of_transmembrane_TNF_α_mediated_cytotoxicity_ L2 - https://doi.org/10.1189/jlb.1209812 DB - PRIME DP - Unbound Medicine ER -