Proteasome dysfunction disrupts adipogenesis and induces inflammation via ATF3

Area of Science:

• Cellular Biology
• Molecular Biology
• Metabolic Diseases

Background:

• Proteasomal activity is vital for cellular proteostasis and function.
• Mutations in proteasome subunits cause proteasome-associated autoinflammatory syndromes (PRAAS), leading to lipodystrophy and fevers.
• The cell-intrinsic pathways underlying PRAAS symptoms, particularly in adipose tissue, remain unclear.

Purpose of the Study:

• To investigate the impact of proteasome subunits Psmb4 and Psmb8 on brown adipocyte differentiation, function, and proteostasis.
• To elucidate the cell-intrinsic mechanisms linking proteasome dysfunction to PRAAS symptoms like lipodystrophy.

Main Methods:

• Downregulation of Psmb4 and Psmb8 using siRNA in immortalized mouse brown pre-adipocytes.
• Analysis of adipogenesis, lipogenesis, lipolysis, inflammation, and respiration in differentiated adipocytes.

Main Results:

• Loss of Psmb4, but not Psmb8, impaired proteostasis and adipogenesis.
• Psmb4 loss reduced proteasome function, partially restored by Nuclear factor, erythroid-2, like-1 (Nfe2l1) activation.
• Increased inflammation and stress markers (Activating transcription factor-3, Atf3) were observed upon Psmb4 loss; simultaneous silencing of Psmb4 and Atf3 restored adipogenesis.

Conclusions:

• Psmb4 is essential for adipocyte development and function.
• Disturbed adipogenesis due to PSMB4 mutations contributes to lipodystrophy in PRAAS patients.
• Nfe2l1 aids proteostasis, while Atf3 mediates inflammation and blocks adipogenesis, highlighting the integrated stress response in adipocytes relevant to PRAAS.