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Open Access Research article

Hax-1 is rapidly degraded by the proteasome dependent on its PEST sequence

Bin Li12, Qingsong Hu12, Ranjie Xu12, Haigang Ren1, Erkang Fei2, Dong Chen1 and Guanghui Wang1*

Author Affiliations

1 Laboratory of Molecular Neuropathology, Department of Pharmacology, Soochow University College of Pharmaceutical Sciences, Suzhou, Jiangsu, 201203, People's Republic of China

2 Laboratory of Molecular Neuropathology and Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui, 230027, People's Republic of China

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BMC Cell Biology 2012, 13:20  doi:10.1186/1471-2121-13-20

Published: 24 July 2012

Abstract

Background

HS-1-associated protein X-1 (Hax-1), is a multifunctional protein that has sequence homology to Bcl-2 family members. HAX-1 knockout animals reveal that it plays an essential protective role in the central nervous system against various stresses. Homozygous mutations in the HAX-1 gene are associated with autosomal recessive forms of severe congenital neutropenia along with neurological symptoms. The protein level of Hax-1 has been shown to be regulated by cellular protease cleavage or by transcriptional suppression upon stimulation.

Results

Here, we report a novel post-translational mechanism for regulation of Hax-1 levels in mammalian cells. We identified that PEST sequence, a sequence rich in proline, glutamic acid, serine and threonine, is responsible for its poly-ubiquitination and rapid degradation. Hax-1 is conjugated by K48-linked ubiquitin chains and undergoes a fast turnover by the proteasome system. A deletion mutant of Hax-1 that lacks the PEST sequence is more resistant to the proteasomal degradation and exerts more protective effects against apoptotic stimuli than wild type Hax-1.

Conclusion

Our data indicate that Hax-1 is a short-lived protein and that its PEST sequence dependent fast degradation by the proteasome may contribute to the rapid cellular responses upon different stimulations.

Keywords:
Hax-1; Proteasome; Ubiquitin; PEST sequence; Bcl-2 family protein