Abstract
Macrophages and dendritic cells dominate early immune responses to lentiviruses. HIV-1 sensing by pathogen recognition receptors induces signaling cascades that culminate in type I alpha/beta interferon (IFN-α/β) induction. IFN-α/β signals back via the IFN-α/β receptors, inducing a plethora of IFN-stimulated gene (ISGs), including ISG15, p53, and p21Cip1 p21 inhibits HIV-1 replication by inactivating the deoxynucleoside triphosphate (dNTP) biosynthesis pathway and activating the restriction factor SAMHD1. p21 is induced by functional p53. ISG15-specific isopeptidase USP18 negatively regulates IFN signaling. We showed previously that USP18 contributes to HIV-1 replication by abrogating p21 antiviral function. Here, we demonstrate a mechanism by which USP18 mediates p21 downregulation in myeloid cells. USP18, by its protease activity, accumulates misfolded p53, which requires ISG15 for its degradation. Depletion of ISG15 causes accumulation of misfolded dominant negative p53, which enhances HIV-1 replication. This work clarifies the function and consequences of p53 modification by ISG15 and implicates USP18 in HIV-1 infection and potentially in carcinogenesis.IMPORTANCE HIV-1 has evolved many strategies to circumvent the host's antiviral innate immune responses and establishes disseminated infection; the molecular mechanisms of these strategies are not entirely clear. We showed previously that USP18 contributes to HIV-1 replication by abrogating p21 antiviral function. Here, we demonstrate a mechanism by which USP18 mediates p21 downregulation in myeloid cells. USP18, by its protease activity, accumulates misfolded p53, which requires ISG15 for clearance. Depletion of ISG15 causes accumulation of misfolded dominant negative p53, which supports HIV-1 replication. This work clarifies the function and consequences of p53 modification by ISG15 and implicates USP18 in HIV-1 infection and potentially in carcinogenesis.
Highlights
Macrophages and dendritic cells dominate early immune responses to lentiviruses
The enhanced human immunodeficiency virus type 1 (HIV-1) replication was mediated by downregulation of p21, which correlated with increased deoxynucleoside triphosphate (dNTP) levels and phosphorylation of the inactive form of SAMHD1 [69]
To understand the molecular mechanisms behind USP18-mediated downregulation of p21, we investigated p21 mRNA and protein expression (Fig. 1A and B) as well as downstream effector proteins of p21 in phorbol myristate acetate (PMA)-differentiated wild-type and SAMHD1 knockout (KO) THP-1.USP18 cells (Fig. 1C)
Summary
Macrophages and dendritic cells dominate early immune responses to lentiviruses. HIV-1 sensing by pathogen recognition receptors induces signaling cascades that culminate in type I alpha/beta interferon (IFN-␣/) induction. Depletion of ISG15 causes accumulation of misfolded dominant negative p53, which enhances HIV-1 replication. P53 expression and activity are regulated by several posttranslational modifications, including ubiquitination, acetylation, phosphorylation, and ISGylation, all of which likely impact p21 induction and function. USP18 depletion by experimental knockout enhances JAK/STAT (signal transducer and activator of transcription) signaling and increases ISGs, resulting in upregulated levels of protein ISGylation [59, 65,66,67,68]. The enhanced HIV-1 replication was mediated by downregulation of p21, which correlated with increased dNTP levels and phosphorylation of the inactive form of SAMHD1 [69]. We investigated the molecular mechanisms behind the USP18-mediated downregulation of p21 and its resultant elevation of dNTP levels and increased phosphorylated SAMHD1 in the myeloid THP-1 and BlaER1 cells
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