An Update on the Role and Mechanisms of TPL2 in Pathogenic Microbial Infection

Review Article

Austin Immunol. 2019; 4(1): 1017.

An Update on the Role and Mechanisms of TPL2 in Pathogenic Microbial Infection

Jun-Hong H, Ming-Hao Y, Xue-Gang Z, Chao- Chao S, Da-Jun Z, Ke-Shan Z*, Hai-Xue Z and Xiang-Tao L

State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agriculture Science, Lanzhou, China

*Corresponding author: Zhang Ke-Shan, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Xujiaping, Lanzhou, PR China

Received: May 16, 2019; Accepted: July 19, 2019; Published: July 26, 2019

Abstract

Tumor progression locus 2 (TPL2) is a serine-threonine kinase that is essential for the activation of the MAPK/MEK1/2-ERK1/2 signaling pathway. It is also a major host immunity regulator and plays a critical role in host immune responses. In order to further elucidate the effects of TPL2 in pathogenic microbial infections, the effects and underlying mechanisms of TPL2 in the pathogenic infections, such as that of the virus, bacteria, and parasites were reviewed. Here, we provide an overview of the multifaceted functions of TPL2 and the molecular mechanisms in pathogenic microbial infections.

Keywords: TPL2; Pathogenic microbial infection; Regulation mechanism; Research advances

Abbreviations

TPL2: Tumor Progression Locus 2; KD: The Kinase Domain; PRR: Pattern Recognition Receptor; PAMPs: Pathogen-Associated Molecular Patterns; IKKβ: IK Kinase β; Ub: Polyubiquitination; M.Tb: Mycobacterium Tuberculosis; LPS: Lipopolysaccharides; CDI: Clostridium Difficile; DSS: Dextran Sulfate Sodium; GBS: Group B Streptococcus; DC: Dendritic Cells.

TPL2 Gene

Tumor progression locus 2 (TPL2) is a serine-threonine kinase that belongs to the protein kinase MAP3K family. Miyoshi et al. initially identified Cot (Cancer Osaka Thyroid) as an oncogene in the early 1990s from the SHOK hamster embryonic cell line that was transfected with the DNA from human thyroid carcinoma cell lines [1]. The rat homolog of Cot was named as TPL2. The two translation initiation sites of TPL2 (M1 and M30) give rise to equal molar levels of the 58-kDa (p58) and 52-kDa (p52) proteins. TPL2 is a 467-Amino Acid (AA) cytoplasmic protein, comprising of three parts: the aminoterminus (N-terminus), the kinase domain (138AA–388AA), and the carboxy-terminus (C-terminus), and the C-terminal degradation determinant (degron, 435aa-457aa) is very important for the protein stability of TPL2 (Figure 1). However, removal of the C-terminal domain appears to activate transforming potential of TPL2 by two mechanisms. First, C-terminal truncation increases the specific kinase activity of TPL2, and it has been suggested that the C-terminal may modulate TPL2 catalytic activity by folding back onto the kinase domain [3-4]. Second, C-terminal truncation removes a degron sequence (amino acids 435-457) that promotes the proteolysis of TPL-2 by the proteasome [4]. The C-terminal truncated sequence “degron” (435-457) has elevated kinase-specific activities, suggesting that this region could inhibit the kinase activities of TPL2 [5].