Nuclear import of proteins with nuclear localization signals (NLSs) is mediated by shuttling carriers, the importins. Some cargoes display more than a single NLS, and among these are homeodomain proteins such as Arx, which is critical for development of multiple tissues. Arx has two functional NLSs. The present studies show that several pathways can import Arx via its NLS2, which is within its DNA binding homeodomain. Using an in vitro nuclear import assay, we show that import of Arx via NLS2 can be mediated by importin ␤1, importin 9, or importin 13, with binding being strongest to importin ␤1. All binding is sensitive to RanGTP. Experiments based on precise domain deletions indicate that NLS2 binds imp␤1, imp9, and imp13 and includes both an importin binding subdomain and a regulatory subdomain with arginine residues being important for function. Moreover, Arx can be co-precipitated with these importins when NLS2 is present. Although nuclear import of Arx can be mediated by these three importin ␤s, importin ␤1 seems to play the major role judging from in vivo small interfering RNA ablations and the in vitro import assay. This is the first evidence to show the role of importin ␤1 in nuclear import of paired-type homeodomain proteins. We propose a novel and possibly quite general mechanism for nuclear import of paired-type homeodomain proteins which is critical for development.Precise nucleocytoplasmic distribution of the homeodomain superfamily of transcription factors is critical for development. Several studies have demonstrated that NLS activity resides within the 60-amino acid DNA binding homeodomain itself, which is composed of three helices (1, 2). The "paired type" subgroup of the superfamily is characterized by a set of highly conserved residues. There are 26 members of this subgroup in man. The aristaless-related homeobox (ARX) 4 protein, a paired-type homeodomain containing protein, is mutated in multiple human conditions (3-5). ARX is expressed most strongly in the brain (6) and is important for development of the forebrain, pancreas, and testis (7). Arx proteins are highly conserved (Fig. 1) and contain 562 amino acids (564 amino acids in mouse) with four poly(A) (alanine) tracts of variable length, a paired-type homeodomain, and a conserved "aristaless" domain (8). Endogenous Arx was found in the nucleus of some types of nerve cells (9, 10). Because Arx has a molecular mass larger than 60 kDa, its nuclear import is likely to be signal-dependent. Three putative basic NLSs in Arx have been proposed (8, 11): NLS1 from aa 82 to 89, BC1 from aa 327 to 334, and BC2 from aa 381 to 388 (Fig. 1). It is not clear whether or how these putative NLSs function in the nuclear localization of Arx.As for other trinucleotide-repeat-containing genes (12, 13), the first poly(A) tract can expand in Arx. Expansion of this tract or loss of the 3Ј aristaless domain in Arx are both associated with infantile spasms syndrome and mental retardation (14, 15). Moreover, expansion of the first poly(A) tract of Arx results in for...

No abstract

Objective Hepatitis B virus infection is a major social and economic burden in developing countries, especially in China. We aimed to evaluate the effects of hepatitis B surface antigen (HBsAg) positive status on the pregnancy outcomes in the Chinese population. Methods This retrospective cohort study was performed using data from the Medical Birth Registry of Xiamen, China, from January 2011 to March 2018. Multivariate logistic regression analysis was used to assess the association between the HBsAg status and pregnancy outcomes. Results This study included 3,789 HBsAg-positive women and 29, 648 non-exposed women. The HBsAg-positive pregnant women were slightly older in age (29.3±4.3 vs. 28.9±4.4, P< 0.001). Additionally, pregnant women with a positive HBsAg status had higher odds of gestational diabetes mellitus (GDM) (adjusted odds ratio [aOR], 1.13; 95% confidence interval [CI], 1.03-1.23), and cesarean delivery (aOR, 1.12; 95%CI, 1.03-1.21). The risk of infants being large or small-for-gestational age, having low-birth weight, and of macrosomia, preterm birth, and stillbirth did not differ significantly between the HBsAg-positive and-negative women. Conclusion In Xiamen, China, the slightly higher risk of GDM and cesarean section in women positive for HBsAg should not be neglected. Further studies should be conducted to evaluate the effects of HBsAg positivity on the pregnancy outcomes in different ethnic populations.

Ubiquitin-dependent proteolysis is mediated by the proteasome. To understand the structure and function of the human 26S proteasome, we cloned complete ORFs of 32 human proteasome subunits and conducted a yeast two-hybrid analysis of their interactions with each other. We observed that there are 114 interacting-pairs in the human 26S proteasome. About 10% (11/114) of these interacting-pairs was confirmed by the GST-pull down analysis. Among these observed interacting subunits, 58% (66/114) are novel and the rest 42% (48/114) has been reported previously in human or in other species. We observed new interactions between the 19S regulatory particle and the beta-rings of the 20S catalytic particle and therefore proposed a modified model of the 26S proteasome.

No abstract