Cytoplasmic transduction peptide (CTP): New approach for the delivery of biomolecules into cytoplasm in vitro and in vivo

Kim, Daeyou; Jeon, Choon-Ju; Kim, Jeong‐Hwan; Kim, Mi-Seon; Yoon, Choon Sik; Choi, In‐Soo; Kim, Sung Hoon; Bae, Yong-Soo

doi:10.1016/j.yexcr.2005.12.029

Cited by 82 publications

(85 citation statements)

References 62 publications

(123 reference statements)

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“…In comparison with PTD, CTP and its fusion partners exhibited a clear preference for cytoplasmic localization, and also markedly enhanced membrane transduction potential. 39,40 By constructing recombinant protein and cell-penetrating peptide, different proteins and polypeptides were delivered into a variety of cells in vivo and in vitro. 41,42 HBcAg 18-27 epitope has been shown to be able to induce HBV-specific CTL response and thus is a potential for the therapeutic design of chronic HBV infection.…”

Section: Ctp-hbcag 18-27 -Tapasin Induces Hbv-specific Ctls X Chen Et Almentioning

confidence: 99%

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

Chen

Tang

Zhang

et al. 2014

Laboratory Investigation

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HBV-specific cytotoxic T-lymphocyte (CTL) activity has a very important role in hepatitis B virus clearance. Present studies suggest that Tapasin, a endoplasmic reticulum (ER) chaperone, stabilizes the peptide-receptive MHC I conformation, allowing peptide exchange and increasing more peptides to be translocated into the ER. We have previously testified that cytoplasmic transduction peptide (CTP)-HBcAg 18-27 -Tapasin fusion protein could enter cytoplasm of dendritic cells, and enhance T cells' response to generate specific CTLs efficiently in vitro. In the present study, we evaluated specific immune responses of CTP-HBcAg 18-27 -Tapasin fusion protein in HLA-A2 transgenic mice (H-2K b ) and anti-viral ability in HBV transgenic mice, and explored the mechanisms probably involved in. The studies showed that CTP-HBcAg 18-27 -Tapasin not only increased production of cytokine IFN-g and interleukin-2 (IL-2), compared with CTP-HBcAg 18-27 , HBcAg 18-27 -Tapasin, and PBS, but also significantly induced the higher percentages of IFN-g þ CD8 þ T cells and specific CTL responses in HLA-A2 transgenic mice. Moreover, enhancement of specific CTL activity induced by the fusion protein reduced HBV DNA and hepatitis B surface antigen (HBsAg) levels and decreased the expression of HBsAg and hepatitis B core antigen (HBcAg) in liver tissue of HBV transgenic mice. In addition, CTP-HBcAg 18-27 -Tapasin could upregulate the expression of JAK2, Tyk2, STAT1, and STAT4 in T lymphocytes in HLA-A2 transgenic mice splenocytes. However, there was no significant difference on the expressions of JAK1, JAK3, and STAT6 between each group. In conclusion, CTP-HBcAg 18-27 -Tapasin fusion protein could enhance not only the percentages of CTLs but also induce robust specific CTL activity and inhibits hepatitis B virus replication in vivo, which was associated with activation of the JAK/STAT signaling pathway. Hepatitis B virus (HBV) infection remains a global problem, despite the effectiveness of the HBV vaccines in preventing infection. Although the factors that contribute to the clearance of the virus in acute self-limiting HBV infection or to the persistence of the virus in chronic HBV infection are not completely clear, increasing evidence suggests that host immune responses are an important factor in determining the outcome of HBV infection. 1,2 Acute individuals develop a strong, polyclonal, multispecific cytotoxic T-lymphocyte (CTL) response and a polyclonal T helper (Th) cell response to the virus typically, while these responses are markedly attenuated in chronically infected patients. 3,4 Persistent HBV infection is characterized by a weak adaptive immune response, thought to be due to inefficient CD4 þ T-cell priming in the early stage of virus infection and subsequent development of a quantitatively and qualitatively ineffective CD8 þ T-cell response. Studies of HBV infection in woodchucks and chimpanzees, as well as patients, are suggesting that multiple and frequent administration of the vaccine may be advisable in treatment of chronic...

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Section: Ctp-hbcag 18-27 -Tapasin Induces Hbv-specific Ctls X Chen Et Almentioning

confidence: 99%

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

Chen

Tang

Zhang

et al. 2014

Laboratory Investigation

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“…Better transduction of tamed PTD-4 was reasoned on obtaining a robust α-helical structure by substituting alanines for basic amino acids in the wild type PTD [80]. Further, another variant of PTD generated by substitutions, known as cytoplasmic transduction peptide (CTP), effectively delivered the cargo into the cytoplasm [81] (Table 2). Interestingly, CTP fusion protein in vivo showed delivery of fusion protein to liver and lymph nodes, but native PTD (as a fusion protein) failed to do so [81,82].…”

Section: Potential Of Ptd-fusion Protein Transduction In Vivomentioning

confidence: 99%

“…Further, another variant of PTD generated by substitutions, known as cytoplasmic transduction peptide (CTP), effectively delivered the cargo into the cytoplasm [81] (Table 2). Interestingly, CTP fusion protein in vivo showed delivery of fusion protein to liver and lymph nodes, but native PTD (as a fusion protein) failed to do so [81,82]. Moreover, "tamed" PTD i.e., CTP, delivered the fusion protein more efficiently than did PTD.…”

Section: Potential Of Ptd-fusion Protein Transduction In Vivomentioning

confidence: 99%

“…Upon treatment with endosomal releasing polymer, poly-(propylacrylic acid), the fusion protein is released in the cytoplasm [128]. Similar to PTD, CTP (a variant of PTD)-mediated delivery was inhibited by treatment of cells with heparinase III and the entry mechanism has currently been assigned to lipid raft mediated endocytosis [81]. On the other hand, CTP-mediated transduction was not affected by chloroquine, which markedly enhanced PTD transduction, indicating that CTP-based fusion protein is released into the cytoplasm while PTD-fusion protein is retained in endosomes and lysosomes [81].…”

Section: Mechanism Of Ptd Internalizationmentioning

confidence: 99%

“…Similar to PTD, CTP (a variant of PTD)-mediated delivery was inhibited by treatment of cells with heparinase III and the entry mechanism has currently been assigned to lipid raft mediated endocytosis [81]. On the other hand, CTP-mediated transduction was not affected by chloroquine, which markedly enhanced PTD transduction, indicating that CTP-based fusion protein is released into the cytoplasm while PTD-fusion protein is retained in endosomes and lysosomes [81]. Interestingly, a recent study has also shown localization of PTD-NP fusion protein in the transGolgi network as well, where efficient processing of influenza virus-NP fusion protein for antigen presentation by the proteolytic protease furin in the trans-Golgi occurred [129].…”

Section: Mechanism Of Ptd Internalizationmentioning

confidence: 99%

See 2 more Smart Citations

The taming of the cell penetrating domain of the HIV Tat: Myths and realities

Chauhan

Tikoo²,

Kapur

et al. 2007

Journal of Controlled Release

153

136

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Protein transduction with cell penetrating peptides over the past several years has been shown to be an effective way of delivering proteins in vitro and now several reports have also shown valuable in vivo applications in correcting disease states. An impressive bioinspired phenomenon of crossing biological barriers came from HIV transactivator Tat protein. Specifically, the protein transduction domain of HIV-Tat has been shown to be a potent pleiotropic peptide in protein delivery. Various approaches such as molecular modeling, arginine guanidinium head group structural strategy, multimerization of PTD sequence and phage display system have been applied for taming of the PTD. This has resulted in identification of PTD variants which are efficient in cell membrane penetration and cytoplasmic delivery. Inspite of these state of the art technologies, the dilemma of low protein transduction efficiency and target specific delivery of PTD fusion proteins remains unsolved. Moreover, some misconceptions about PTD of Tat in the literature require considerations. We have assembled critical information on secretory, plasma membrane penetration and transcellular properties of Tat and PTD using molecular analysis and available experimental evidences.

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