Critical Role of UBXN6 in Autophagy Induction and Inflammation Control in Macrophages

Background

The innate immune system serves as the first line of defense against pathogen invasion and inflammatory responses. Monocytes and macrophages, as key cell types in the innate immune system, play critical roles during infection and inflammation. However, when these cells become dysfunctional, harmful inflammation may ensue. Thus, understanding the mechanisms by which monocytes and macrophages regulate inflammation and innate immunity is vital for developing therapeutic interventions against inflammatory diseases such as sepsis. While progress has been made in this area, the mechanisms maintaining the delicate balance between inflammation and innate immune responses remain incompletely understood.

Proteostasis, the maintenance of protein homeostasis, is central to cellular health and involves processes such as autophagy, endoplasmic reticulum-associated degradation (ERAD), and proteasome-mediated degradation. Autophagy, a lysosomal pathway that degrades large protein aggregates and damaged organelles, is a key regulator of immune and inflammatory responses. ERAD, on the other hand, maintains protein quality by degrading misfolded or unfolded proteins. Valosin-containing protein (VCP)/p97 is an ATPase critical for processes such as autophagy, ERAD, gene expression, and organelle biogenesis. UBXN6, a cofactor of VCP/p97, has been implicated in various cellular processes, but its role in the innate immune system remains poorly explored.

Research Source

This study was conducted by Young Jae Kim, Sung-Gwon Lee, So Young Park, and others from institutions including Chungnam National University College of Medicine (Republic of Korea), the U.S. National Institutes of Health, and Chonnam National University (Republic of Korea). The findings were published in Cellular & Molecular Immunology on October 23, 2024, in an article titled “Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages.”

Experimental Flow and Key Findings

1. Upregulation of UBXN6 in Sepsis Patients

The study first analyzed gene expression changes in peripheral blood mononuclear cells (PBMCs) from sepsis patients via RNA sequencing. UBXN6 was significantly upregulated in sepsis patients, showing a negative correlation with inflammatory gene expression and a positive correlation with autophagy-related genes such as FOXO3. This suggests that UBXN6 acts as a crucial regulator of inflammation in sepsis by modulating autophagy.

2. UBXN6 Deficiency Exacerbates Inflammatory Responses in Macrophages

Using myeloid-specific UBXN6 knockout mice, the study demonstrated that UBXN6-deficient macrophages exhibited heightened inflammatory responses upon lipopolysaccharide (LPS) stimulation. This included increased expression of proinflammatory cytokines such as TNF and IL-1β, as well as elevated mitochondrial oxidative stress. Additionally, both autophagy and ERAD pathways were impaired in UBXN6-deficient macrophages.

3. UBXN6 Regulates Inflammation via Autophagy and ERAD Pathways

The study showed that UBXN6 deficiency led to a failure in autophagosome formation under autophagic stimuli such as starvation and LPS. Moreover, UBXN6-deficient macrophages exhibited reduced expression of ERAD-related genes such as SEL1L and SYVN1, leading to increased mitochondrial oxidative stress. This underscored the role of UBXN6 in dampening inflammation by coordinating autophagy and ERAD.

4. UBXN6 Orchestrates Immunometabolic Reprogramming

Metabolomic analysis revealed a shift toward aerobic glycolysis in UBXN6-deficient macrophages, accompanied by a significant increase in intracellular branched-chain amino acids (BCAAs). These metabolic changes activated the mTOR pathway, inhibiting the nuclear translocation of the transcription factor TFEB and impairing lysosomal biogenesis. This highlights UBXN6’s critical involvement in immunometabolic regulation.

5. UBXN6 Protects Against Inflammatory Damage In Vivo

UBXN6-deficient mice displayed heightened sensitivity to LPS-induced inflammation, resulting in higher mortality rates, pronounced inflammation in organs like the lung and spleen, and greater mitochondrial damage in acute lung injury models. These findings demonstrate UBXN6’s protective role against systemic inflammation and mitochondrial dysfunction in vivo.

Conclusions and Implications

This study highlights the essential role of UBXN6 in controlling macrophage-mediated inflammation and maintaining mitochondrial and cellular homeostasis. UBXN6 facilitates autophagy and ERAD pathways to suppress inflammatory responses. Furthermore, UBXN6 modulates immunometabolic pathways, influencing cellular energy metabolism, mitochondrial health, and lysosomal biogenesis to ensure appropriate inflammatory control. These findings could inform the development of novel therapeutic strategies targeting UBXN6 for inflammatory diseases such as sepsis.

Research Highlights

1. UBXN6 is Upregulated in Sepsis: UBXN6 expression is significantly higher in sepsis patients and correlates negatively with inflammatory gene expression, pointing to its potential regulatory role in inflammation.

2. UBXN6 Promotes Autophagy and ERAD: Deficiency of UBXN6 in macrophages disrupts autophagy and ERAD, amplifying oxidative stress and inflammation.

3. UBXN6 Regulates Immunometabolism: By shifting metabolism toward aerobic glycolysis and modulating BCAA levels, UBXN6 influences mTOR signaling and lysosomal biogenesis.

4. UBXN6 Provides In Vivo Protection: Loss of UBXN6 exacerbates inflammation and mitochondrial damage in animal models of acute inflammation and sepsis.

Research Significance

This study not only elucidates a novel function of UBXN6 in macrophages but also deepens our understanding of the pathophysiology of sepsis and other inflammatory diseases. Targeting UBXN6 could represent a new therapeutic approach for alleviating inflammation and improving outcomes in inflammatory conditions like sepsis.