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UBC Theses and Dissertations

ABCF1 is a novel E2 ubiquitin-conjugating enzyme that controls Toll-like receptor-mediated innate immune responses and cytokine storm during sepsis Arora, Hitesh

Abstract

Immune responses are tightly controlled mechanisms that serve as the primary means by which invading pathogens are eradicated. These mechanisms are governed by the action of several proteins that, when activated, regulate a cascade of downstream effectors in immune cells that help control and, often eliminate the infection. We have discovered a protein, ABCF1, which regulates this immune response cascade through Toll-like receptor (TLR) signaling and helps maintain cellular homeostasis. ABCF1 is the only known member of the ATP-Binding Cassette (ABC) superfamily that lacks a trans-membrane domain and thus doesn’t function as a transporter. Previous studies on ABCF1 indicate a role for this protein in DNA sensing mechanisms and in the pathophysiology of rheumatoid arthritis and autoimmune pancreatitis. We have discovered that ABCF1 is the sole member of the ABC superfamily possessing E2 ubiquitin-conjugating enzyme activity and exclusively regulates TLR4 endocytosis in murine macrophages. In our studies, ABCF1 was found to target Spleen Tyrosine Kinase (SYK) and TNF Receptor Associated Factor (TRAF3) proteins for K63-linked polyubiquitination, thereby regulating the shift from MyD88-dependent to TRIF-dependent signaling. We also observed that ABCF1 negatively regulates MyD88-dependent pro-inflammatory cytokine production in TLR2 and TLR9 signaling, thereby controlling macrophage polarization to the M2 phenotype. ABCF1 was also found to control viral immune responses by regulating OAS1a enzyme activity and negatively regulating ABCE1 thereby modulating RNase L activation. ABCF1 also seemed to control FcγR II-mediated phagocytosis through phosphorylation of SRC Family Kinases (SFKs). Our data also revealed that ABCF1 negatively regulates cytokine storm during the inflammatory phase of sepsis. It associates with TRAF3 and targets TRAF3 for K63-linked poly ubiquitination, thereby controlling the shift from inflammatory phase to immune compromised phase during sepsis. ABCF1 haploinsufficiency was found to trigger lethal renal circulatory dysfunction, which drastically reduced survival rates during the inflammatory phase of sepsis. We herein report the discovery of a novel E2 enzyme, ABCF1, whose E2 ubiquitin-conjugating activity controls TLR-mediated inflammation and cytokine storm during sepsis in murine macrophages.

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