SerpinB2 Is an Inducible Host Factor Involved in Enhancing HIV-1 Transcription and Replication

Abstract

The serine protease inhibitor SerpinB2 (plasminogen activator inhibitor-2) is a major product of activated monocytes and macrophages and is substantially induced during most inflammatory processes. Distinct from its widely described extracellular role as an inhibitor of urokinase plasminogen activator, SerpinB2 has recently been shown to have an intracellular role as a retinoblastoma protein (Rb)-binding protein that inhibits Rb degradation. Here we show that HIV-1 infection and gp120 treatment of human peripheral blood mononuclear cells resulted in induction of SerpinB2. Furthermore, SerpinB2 expression in THP-1 monocyte/macrophage, Jurkat T, and HeLa cell lines increased replication of HIV-1 and enhanced transcription from the HIV-1 long terminal repeat (LTR) promoter by 3-10-fold. Increased HIV-1 gene expression and transcription was also observed in activated macrophages from SerpinB2 ؉/؉ mice compared with macrophages from SerpinB2 ؊/؊ mice. The SerpinB2-mediated elevation of Rb protein levels appeared to be responsible for enhancing transcription from the core promoter region of the LTR by relieving HDM2-mediated inhibition of Sp1 and/or by increasing the Sp1/Sp3 expression ratios. This is the first report associating HIV-1 replication with SerpinB2 expression and illustrates that SerpinB2 is a potentially important inducible host factor that significantly promotes HIV-1 replication.SerpinB2, also known as plasminogen activator inhibitor type-2 (PAI-2), 2 is one of the most abundant proteins of activated monocytes and macrophages, whose expression is substantially up-regulated during most inflammatory processes (1, 2). SerpinB2 is also induced following infection with a range of parasitic (3, 4), viral (5-8), and bacterial (9 -12) pathogens. Although SerpinB2 is widely described as an inhibitor of the extracellular urokinase plasminogen activator, the evidence that SerpinB2 has a major physiological role in the regulation of plasminogen activation is not compelling (13). SerpinB2 is a member of the Clade B or ovalbumin-like serine protease inhibitor (ov-serpin) subgroup of serpins, which lack a classical secretory signal peptide and are frequently found to reside intracellularly with a cytoplasmic or nucleocytoplasmic distribution (14). SerpinB2 has recently been shown to have an intranuclear activity as a retinoblastoma protein (Rb)-binding protein (15-18). SerpinB2 expression inhibited Rb degradation, which resulted in increased Rb protein levels. This activity required both (i) the C-D interhelical region of SerpinB2, which mediates Rb binding, and (ii) the reactive site loop (RSL), which mediates the protease inhibitory activity of SerpinB2. The SerpinB2-mediated increase in Rb protein levels was found to enhance Rb-mediated activities, such as repression of E2F-1-dependent gene expression and promotion of G 1 cell cycle arrest (15). SerpinB2 expression has also been shown to influence transcription of mammalian (15, 19) and viral genes (16), with the latter two studies illustrating that this activity ...

Spontaneous Irs1 passenger mutation linked to a gene-targeted SerpinB2 allele

“…007234, http://jaxmice.jax.org/strain/007234.html; Jackson Laboratory) has been deposited at Jackson Laboratory and has been distributed to other investigators. All subsequent studies and reports from other groups (14,15,(40)(41)(42) were confined to the 10G3 line. All animal care and experimental procedures complied with the Principles of Laboratory and Animal Care established by the National Society for Medical Research and were approved by the University of Michigan Committee on Use and Care of Animals.…”

A Physiological Function of Inflammation-Associated SerpinB2 Is Regulation of Adaptive Immunity

“…Ov-serpins lack a classical secretory signal peptide and are frequently found to have cytoplasmic or nucleocytoplasmic distributions and functions (1,2). SerpinB2 is induced during many inflammatory processes and infections (3)(4)(5)(6)(7) and is one of the most upregulated proteins of activated monocytes/macrophages representing up to 1% of total protein (7,8). SerpinB2 can also be induced to a lesser extent in fibroblasts and endothelial cells and is constitutively expressed by differentiating keratinocytes, placental trophoblasts (3), adipocytes (9), and a range of tumors (4,10).…”

Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1

“…The induction of PAI-2 is thought to be one component of this response (17). In very many other tissues induction of PAI-2 is also thought to be a response to damage, infection, or inflammation (4,12,52). In addition, PAI-2 expression has been linked to cancer (1, 2), and it seems possible that whereas acute induction is protective, long-term upregulation is potentially a contributory factor in tumorigenesis.…”