Outcomes of a PrEP Demonstration Project with LGBTQ Youth in a Community-Based Clinic Setting with Integrated Gender-Affirming Care.

Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) youth are disproportionately affected by HIV, and young transgender women (YTW) are especially impacted. The purpose of this small demonstration project was to measure pre-exposure prophylaxis (PrEP) adherence in a community-based clinic for LGBTQ youth in which PrEP services are integrated with gender-affirming care. Of the 50 enrolled participants, 38 had a serum drug assay performed after three or more months and 26% of those had laboratory evidence of highly protective levels of medication. Low adherence highlights the need for culturally tailored follow-up efforts and assistance with the structural barriers to health experienced by LGBTQ youth, especially YTW.

Stringent Control of NFE2L3 (Nuclear Factor, Erythroid 2-Like 3; NRF3) Protein Degradation by FBW7 (F-box/WD Repeat-containing Protein 7) and Glycogen Synthase Kinase 3 (GSK3).

The NFE2L3 transcription factor has been implicated in various cellular processes, including carcinogenesis, stress response, differentiation, and inflammation. Previously it has been shown that NFE2L3 has a rapid turnover and is stabilized by proteasomal inhibitors. The mechanisms regulating the degradation of this protein have not been investigated. Here we report ubiquitination of NFE2L3 and demonstrate that F-box/WD repeat-containing protein 7 (FBW7 or FBWX7), a component of Skp1, Cullin 1, F-box containing complex (SCF)-type E3 ligase, is the E3 ligase mediating the degradation of NFE2L3. We showed that FBW7 interacts with NFE2L3 and that dimerization of FBW7 is required for the degradation of the transcription factor. We also demonstrate that the kinase glycogen synthase kinase 3 (GSK3) mediates the FBW7-dependent ubiquitination of NFE2L3. We show phosphorylation of NFE2L3 by GSK3 and its significance in the regulation of NFE2L3 by the tumor suppressor FBW7. FBW7 abrogated NFE2L3-mediated repression of the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene antioxidant response element (ARE). Our findings reveal FBW7 and GSK3 as novel regulators of the NFE2L3 transcription factor and a potential mechanism by which FBW7 might regulate detoxification and the cellular response to stress.