Bik promotes proteasomal degradation to control low-grade inflammation

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, autoimmu...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	The Journal of clinical investigation Jg. 134; H. 4
Hauptverfasser:	Mebratu, Yohannes A., Jones, Jane T., Liu, Congjian, Negasi, Zerihun H., Rahman, Mizanur, Rojas-Quintero, Joselyn, O’Connor, George T., Gao, Wei, Dupuis, Josée, Cho, Michael H., Litonjua, Augusto A., Randell, Scott, Tesfaigzi, Yohannes
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 15.02.2024
Schlagworte:	Allergic reaction Allergy Animals Apoptosis Apoptosis Regulatory Proteins Apoptotic proteins Autoimmunity Development and progression Diseases Emphysema Emphysema, Pulmonary Female Genetic aspects Genetic engineering Health aspects Heart diseases Hexosyltransferases Humans Inflammation Inflammation - genetics Male Massachusetts Mice Mitochondrial Proteins New Mexico Nuclear Proteins Physiological aspects Proteasome Endopeptidase Complex - genetics Proteins Proteolysis Proto-Oncogene Proteins c-bcl-2 Single nucleotide polymorphisms Tetracycline Tetracyclines United States New Mexico Massachusetts Inflammation NF-kappaB Peptides Apoptosis
ISSN:	1558-8238, 0021-9738, 1558-8238
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: YAM and JTJ contributed equally to this work.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI170594