dsRNA binding protein PACT/RAX in gene silencing, development and diseases

doi:10.1007/s11515-014-1325-z

Front. Biol.

2014, Vol. 9

Issue (5) : 382-388 https://doi.org/10.1007/s11515-014-1325-z

REVIEW

dsRNA binding protein PACT/RAX in gene silencing, development and diseases

Yue YONG¹,Jia LUO^2,^*(

),Zun-Ji KE^1,^3,^*(

)

1. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
2. Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA
3. Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China

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Abstract

PACT (Protein kinase, interferon-inducible double stranded RNA dependent activator) and its murine ortholog RAX (PKR-associated protein X) were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase (PKR). Endogenous PACT/RAX activates PKR in response to diverse stress signals such as serum starvation, and peroxide or arsenite treatment. PACT/RAX heterodimerized with PKR and activated it with its third motif in the absence of dsRNA. The activation of PKR leads to enhanced eIF2α phosphorylation followed by apoptosis or inhibition of growth. Besides the role of activating PKR, PACT is associated with a ~500 kDa complex that contains Dicer, hAgo2, and TRBP (TAR RNA binding protein) and it associates with Dicer to facilitate the production of small interfering RNA. PACT/RAX plays an important role in diverse physiological and pathological processes. Pact^-/- mice exhibit notable developmental abnormalities including microtia, with craniofacial ear, and hearing defects. Pact^-/- mice had smaller body sizes and fertility defects, both of which were caused by defective pituitary functions. It was found that dRAX disrupted fly embryos homozygous, displayed highly abnormal commissural axon structure of the central nervous system, and 70% of the flies homozygous for the mutant allele died prior to adulthood. Using high density SNP genotyping arrays, it was found that a mutation in PRKRA (the PACT/RAX gene) is the causative genetic mutation in DYT16, a novel autosomal recessive dystonia-parkinsonism syndrome in Brazilian patients.

Keywords PACT/RAX PKR TRBP Dicer DYT16

Corresponding Author(s): Jia LUO

Online First Date: 11 August 2014 Issue Date: 11 October 2014

Cite this article:

Yue YONG,Jia LUO,Zun-Ji KE. dsRNA binding protein PACT/RAX in gene silencing, development and diseases[J]. Front. Biol., 2014, 9(5): 382-388.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-014-1325-z
https://academic.hep.com.cn/fib/EN/Y2014/V9/I5/382

Fig.1 Role of PACT/RAX in the development and diseases. PACT/RAX is activated by various cellular stresses and interacts with PKR, resulting in eIF2α phosphorylation and subsequent inhibition of protein synthesis and induction of apoptosis or growth inhibition. RAX/PACT-PKR interaction promotes p53 sumoylation, leading to G₁ cell cycle arrest. PACT/RAX associates with TRBP, Dicer and Ago2 and regulates siRNA/miRNA generation and gene silencing. PACT/RAX knockout or mutation leads to diseases and serious development defects through unknown mechanisms. PACT/RAX is an important stress responsive protein and plays important in cell physiology and development.

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