Bik promotes proteasomal degradation to control low-grade inflammation
Yohannes A. Mebratu, … , Scott Randell, Yohannes Tesfaigzi
Yohannes A. Mebratu, … , Scott Randell, Yohannes Tesfaigzi
Published December 19, 2023
Citation Information: J Clin Invest. 2024;134(4):e170594. https://doi.org/10.1172/JCI170594.
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Bik promotes proteasomal degradation to control low-grade inflammation

Abstract

Although chronic low-grade inflammation does not cause immediate clinical symptoms, over the longer term, it can enhance other insults or age-dependent damage to organ systems and thereby contribute to age-related disorders, such as respiratory disorders, heart disease, metabolic disorders, autoimmunity, and cancer. However, the molecular mechanisms governing low-level inflammation are largely unknown. We discovered that Bcl-2–interacting killer (Bik) deficiency causes low-level inflammation even at baseline and the development of spontaneous emphysema in female but not male mice. Similarly, a single nucleotide polymorphism that reduced Bik levels was associated with increased inflammation and enhanced decline in lung function in humans. Transgenic expression of Bik in the airways of Bik-deficient mice inhibited allergen- or LPS-induced lung inflammation and reversed emphysema in female mice. Bik deficiency increased nuclear but not cytosolic p65 levels because Bik, by modifying the BH4 domain of Bcl-2, interacted with regulatory particle non-ATPase 1 (RPN1) and RPN2 and enhanced proteasomal degradation of nuclear proteins. Bik deficiency increased inflammation primarily in females because Bcl-2 and Bik levels were reduced in lung tissues and airway cells of female compared with male mice. Therefore, controlling low-grade inflammation by modifying the unappreciated role of Bik and Bcl-2 in facilitating proteasomal degradation of nuclear proteins may be crucial in treating chronic age-related diseases.

Authors

Yohannes A. Mebratu, Jane T. Jones, Congjian Liu, Zerihun H. Negasi, Mizanur Rahman, Joselyn Rojas-Quintero, George T. O’Connor, Wei Gao, Josée Dupuis, Michael H. Cho, Augusto A. Litonjua, Scott Randell, Yohannes Tesfaigzi

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Figure 3

Bik suppresses LPS and allergen-induced inflammation in mice.

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Bik suppresses LPS and allergen-induced inflammation in mice. (A) bik+/+...
(A) bik+/+ and bik–/– mice were instilled with 5 μg LPS intranasally, and neutrophil numbers were compared in the BAL fluid 4 hours later. n = 5/group. (B) TetoBik– and tetoBik+ mice were put on Dox diet for 48 hours, and the expression of Bik was analyzed in the lung tissues by qRT-PCR or immunostaining. Bik mRNA and protein levels were shown by qRT-PCR and immunostaining, respectively. (C) Baseline macrophage levels in the BAL fluid of male and female CCSP-rtTA+TetOBik+ and CCSP-rtTA+TetOBik– mice, 2 male and 3 female in TetOBik– and 4 male and 3 female in CCSP-TetOBik– per group. (D) TetoBik– and TetoBik+ mice were placed on Dox diet for 48 hours and subsequently instilled with 50 μg LPS and lungs harvested; BAL fluid neutrophil numbers were quantified 4 hours later (n = 7/group 4 males and 3 female). (E) Female bik–/– mice were instilled once daily over 2 days with 108 virus particles of Ad-Bik or Ad-GFP, as control, diluted in final volume of 50 μL in PBS. Twenty-four hours later, mice were intranasally instilled with 5 μg LPS and euthanized and BAL fluid neutrophil numbers quantified 24 hours later. n = 4/group. (F) TetoBik– and TetoBik+ mice were placed on Dox diet for 48 hours and subsequently instilled with 10 μg HDM for 5 days (n = 5/group). BAL cell numbers were analyzed 5 days later. Two-tailed Student’s t test was used to compare between 2 groups, and grouped results were analyzed using 2-way ANOVA. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01.