MARCH E3 Ligases: Understudied Regulators of Pulmonary Immune Function

ABSTRACT: Membrane-associated RING-CH (MARCH) ligases are a family of 11 ubiquitin E3 ligases that regulate protein stability, trafficking, and signaling across diverse cellular contexts. Although MARCH ligases have been studied most extensively in immune regulation, antigen presentation, viral restriction, and cellular homeostasis, their roles in pulmonary biology remain incompletely defined. The lung is a highly specialized environmental interface that must preserve gas exchange while continuously responding to infectious, inflammatory, and sterile insults. These demands require careful regulation of epithelial and endothelial barrier integrity, innate and adaptive immune activation, and tissue repair. Current work suggests that MARCH ligases influence many of these processes by regulating inflammatory responses, cytokine receptors, antiviral signaling mediators, viral proteins, mitochondrial fission or fusion, junctional molecules, ciliary components, and remodeling pathways. In this review, we summarize current knowledge and highlight gaps in the understanding of MARCH ligase expression and function in lung-relevant cell types and disease contexts. Defining how MARCH ligases operate within specific lung compartments may reveal new regulatory mechanisms governing pulmonary immunity, barrier function, host defense, and lung remodeling.