HNRNPD (heterogeneous nuclear ribonucleoprotein D (AU-rich element RNA binding protein 1, 37kDa))

Note	Differential splicing of a single HNRNPD transcript results in four isoforms: p37, p40, p42 and p45.
	Structure of the human HNRNPD gene. Exon positions (red) and sizes (nt-nucleotides) are labelled.
Description	HNRNPD gene is composed of 10 exons, ranging in size from 57 to 497 nt. Eight of 10 exons are localised within the coding region. Exon 1 contains 5' UTR and encodes N-terminal part of the AUF1 protein. Exon 2 encodes the 19-aminoacid insertion of the N-terminal part of the first RNA-binding domain (RBD). This insertion is localised only in isoforms p40 and p45. Exons 3-6 encode the rest of the first RBD, the N-terminal half of the second RBD, the C-terminal half of the second RBD and the glutamine rich region, respectively. Exon 7 encodes the 49-aminoacid insertion localised only in isoforms p42 and p45. The smallest isoform p37, lacks exon 2 and 7. Exon 8 encodes the C-terminal part common to all isoforms and part of the 3' UTR. A TAA nonsense codon is also localised within this exon. Exon 9 contains two additional in-frame stop codons and encodes an alternatively spliced, 107 nt part of the 3' UTR. Exon 10 encodes the rest of 3' UTR and contains an AATAAA polyadenylation signal.
Transcription	Transcription initiation sites were not exactly identified, but there is a TATAA box 175 nt upstream of the 5' end of the human cDNA clone with the longest 5' UTR. The first ATG codon is located in exon 1, at least 250 nt from the 5' end of mRNA.
Pseudogene	One pseudogene according to RefSeq was localised. Localisation: Xq12

	Structure of HNRNPD (AUF1) proteins; RBD1-2, RNA binding domains; Q, glutamine rich element; HNS, Exon 2, 19 amino acids; Exon 7, 49 amino acids.
Description	The family of HNRNPD (AUF1) proteins distinguishes a 37 kDa (p37) core protein, a 40 kDa protein (p40) containing an N-terminal 19 amino acid insertion (exon 2), a 42 kDa protein (p42) exhibiting a C-terminal 49 amino acids insertion (exon 7), and a 45 kDa protein (p45) with insertions of both exon 2 and exon 7. Presence or absence of these alternatively spliced exons confers distinct biological properties to individual AUF1 isoforms. Presence of exon 7 not only affects nucleo-cytoplasmic distribution, but also blocks ubiquitination of p42 and p45. In contrast, the lack of exon 7 targets p37 and p40 to the ubiquitin proteasome pathway, where both isoforms serve as substrates in decay reaction. This results in rapid and selected decay of adenylate-uridylate rich elements (AREs) containing mRNAs. Importantly, absence of exon 2 in p37 and p42 is associated with high affinity binding of these isoforms. The smallest AUF1 isoform p37 posses the strongest mRNA binding affinity, which for other isoforms decreases in following rank of order: p37>p42>p45>p40.
Expression	AUF1 is expressed early in the development. High levels of AUF1 proteins were found in lymphoid tissues, such as spleen and thymus, and lower levels in brain and fetal liver. In adult liver AUF1 was undetectable. In spleen and thymus extracts, isoforms p40 and p45 were more abundant than p37. Isoforms p45 and p40 were most abundant in brain and in fetal liver, respectively. Both mentioned organs lacked expression of p37.
Localisation	AUF1 is predominantly nuclear and is able to shuttle between nucleus and cytoplasm. In the nucleus, AUF1 is found within stable ribonucleoprotein complexes; in the cytoplasm, AUF1 binds to target mRNAs and is often co-localised with the exosome. The triggering of AUF1-mediated degradation is consistent with changes of cellular localisation of this protein. Previous studies demonstrated that blocking of ARE-mediated mRNA decay by heat shock, down-regulation of the ubiquitin-proteasome pathway or by inactivation of the E1 ubiquitinating enzyme all resulted in hnRNPD movement to the nucleus of human HeLa cells. However, the cellular factors and/or events involved in regulating these different activities for AUF1 remain to be defined.
Function	AUF1 is involved in processes of apoptosis, tumorigenesis and development by its interactions with AREs bearing mRNAs. It is able to bind both single stranded DNA and RNA, especially transcripts bearing AREs in their 3' UTR. AUF1 may bind AREs of all classes (I, II and III) and its over-expression noticeably influences the stability of ARE containing mRNAs. AUF1 appears to enhance target mRNA decay, a process that is closely related to the ubiquitination and targeting of AUF1 to the proteasome. AUF1 target mRNAs encode mitogenic, immune response, cancer-associated, stress response, and cell cycle regulatory proteins such as c-fos, c-jun, c-myc, egr-1, interleukins, iNOS, DNMT1, p21, p27, hsp70, MnSOD, catalase, cyclin D1, and cdc25. It was reported that increased level of AUF1 in human erythroleukemic K562 cells, especially isoforms p37AUF1 and p42AUF1, induced ARE-directed mRNA degradation. AUF1 itself does not possess enzymatic activity but may interact and recruit other proteins, including lactate dehydrogenase (LDH), stratifin, ubiquitin-conjugating enzyme E2I, RNA binding proteins NSEP-1, NSAP-1 and IMP-2. NSEP-1 was demonstrated to possess an endoribonuclease activity.
Homology	The human and murine HNRNPD proteins are highly conserved and revealed similarity of 98.9%. The differences are mainly restricted to the N-terminal portion of the protein. The human HNRNPD locus maps to 4q21, and the murine Hnrnpd locus maps to the F region of chromosome 3.

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