p16 (86 amino acids) - late incompletely spliced mRNA
Localization:
Cell nucleolus / nucleus
Extracellular
Function:
Regulatory protein
Viral transcriptional transactivator
Binds to transactivating responsive sequence (TAR) RNA element for
viral transcription initiation and/or elongation from LTR promoter (Ref. #7 & #8)
Upregulates expression of all viral genes
Promotes the elongation phase of HIV-1 transcription, allowing full-length transcripts to be produced (Ref. #9 & #10)
Represses cellular promoters
Additional
Information:
Tat functions early in viral infections
the TAR RNA element forms a hairpin stem-loop structure with a
side bulge; the bulge is necessary for Tat binding and function
the TAR RNA element is located at the 5'-terminus of the HIV RNA genome
Tat is one of two viral regulatory factors (Rev
is the other regulatory factor), and both are necessary for HIV gene expression
In the absence of Tat expression, HIV generates short (less than 100 nucleotides in length) transcripts
Tat may have similarities with prokaryotic anti-termination factors
extracellular TAT can be taken up by cells in culture (Ref. #10)
Tat is essential for viral replication (Ref. #6)
Tat increases the basal activity of LTR, regardless of integration site
Tat acts as a growth factor for Kaposi's Sarcoma (skin cancer) cells
Tat activates expression of many cellular genes including tumour necrosis factor alpha (Ref. #13) and transforming growth factor alpha 1 (Ref. #14)
Tat downregulates expression of some cellular genes by activating expression of bcl-2, and MIP-1 alpha (Ref. #15 & #16)
Stimulation
of polymerase elongation results from interactions between Tat and
serine kinase CDK9, which phosphorylates the carboxyl-terminal domain
of RNA polymerase II (Ref. #11)
Interactions between Tat and cellular co-factor Cyclin T are necessary for recognition of TAR (Ref. #12)
Additional information about HIV-1 Tat can be found in the recent BMC Retrovirology review article (Ref. #17)
Molecular Weight (HXB2): 9837 Da Molecular Weight (Consensus B): 11525 Da
Theoretical pI (HXB2): 9.88 Theoretical pI (Consensus B): 9.53
Gene Description: Tat consists of spliced exons that are separated by 2334
nucleotides, and they are found on two different reading frames. The 5' exon is located on the 2nd reading frame (start:
5831 || end: 6045).
The 3' exon is located on the 1st reading frame (start: 8379 || end:
8469). Tat contains a premature stop codon at position
8424.
Human Tip60 (60 kDa Tat interactive protein) interacts in the nucleus
Human TAK (Tat-associated kinase) is activated by Tat and phosphorylates RNA polymerase II, stimulating elongation.
PKR (double-stranded RNA-activated kinase) phosphorylates two serines and one threonine residues immediately adjacent to the basic region of Tat.
Tat actively binds to the cellular co-factor Cyclin T1, which facilitates recognition of the transactivation response element (TAR) RNA. (Ref. #12)
Interactions between Tat, Cyclin T1 and the serine kinase CDK9
induce phosphorylation of the carboxyl-terminal domain of RNA
polymerase II, which stimulates processive polymerase elongation of
HIV-1 RNA (Ref. #11)
Tat transactivation activity occurs through p300 and CREB-binding protein (CBP), which have histone acetyltransferase activity.
After binding to p300 and CBP, Tat recruits them to integrated viral LTR
p300 and CBP acetylate histones, weakening the histone-DNA interactions, relieving the repressive effects of the chromatin scaffold on the LTR
The 5' exon is located on the 2nd reading frame (start:
5831 || end: 6045).