Crotonylation sensitizes IAPi-induced disruption of latent HIV by enhancing p100 cleavage into p52

Dajiang Li; Morgan G Dewey; Li Wang; Shane D Falcinelli; Lilly M Wong; Yuyang Tang; Edward P Browne; Xian Chen; Nancie M Archin; David M Margolis; Guochun Jiang

doi:10.1016/j.isci.2021.103649

Crotonylation sensitizes IAPi-induced disruption of latent HIV by enhancing p100 cleavage into p52

iScience. 2021 Dec 18;25(1):103649. doi: 10.1016/j.isci.2021.103649. eCollection 2022 Jan 21.

Authors

Dajiang Li¹, Morgan G Dewey¹, Li Wang², Shane D Falcinelli^{1

3}, Lilly M Wong¹, Yuyang Tang¹, Edward P Browne^{1

3

4}, Xian Chen², Nancie M Archin^{1

4}, David M Margolis^{1

3

4}, Guochun Jiang^{1

2}

Affiliations

¹ UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, The University of North Carolina at Chapel Hill, 120 Mason Farm Rd, Genetic Medicine Building, Room 2111, Chapel Hill, NC 27599-7042, USA.
² Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.
³ Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.
⁴ Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.

Abstract

The eradication of HIV infection is difficult to achieve because of stable viral reservoirs. Here, we show that crotonylation enhances AZD5582-induced noncanonical NF-κB (ncNF-κB) signaling, further augmenting HIV latency reversal in Jurkat and U1 cell line models of latency, HIV latently infected primary CD4+ T cells and resting CD4+ T cells isolated from people living with HIV. Crotonylation upregulated the levels of the active p52 subunit of NF-κB following AZD5582. Biochemical analyses suggest that the ubiquitin E3 ligase TRIM27 is involved in enhanced p100 cleavage to p52. When TRIM27 was depleted, AZD5582-induced HIV latency reversal was reduced. TRIM27 small interfering RNA (siRNA) knockdown reduced both p100 and p52 levels without inhibiting p100 transcription, indicating that TRIM27 not only acts on p100 cleavage but also may impact p100/p52 stability. These observations reveal the complexity of HIV transcriptional machinery, particularly of NF-κB.

Keywords: Immunology; Virology.

Abstract

Grants and funding