Document Type

Thesis - Open Access

Award Date

2022

Degree Name

Master of Science (MS)

Department / School

Biology and Microbiology

First Advisor

Jamie Lopez

Abstract

A20 Inhibitor of NF-κB (ABIN1/TNIP1) is a known regulator of TNFα signaling induced cell death and inflammation. The regulatory activity has been attributed to ABIN1’s recruitment of the ubiquitin editing enzyme TNF-α-induced protein 3 (TNFAIP3/A20) to Receptor-interacting serine/threonine-protein kinase 1 (RIPK1). The regulation of RIPK1 by ABIN1 and A20 relies on a third player, linear ubiquitin chain assembly complex (LUBAC), which is involved in the recruitment of ABIN1 to RIPK1. Loss of LUBAC or ABIN1 is embryonic lethal, but loss of A20 is not embryonic lethal. The embryonic lethality due to loss of ABIN1, paired with the lack of lethality with loss of A20, provides evidence that ABIN1 plays a role in cellular regulation beyond its role in recruiting A20 for RIPK1 regulation. We established that ABIN1 binds LC3 and is degraded in an autophagy-dependent manner. We also found that ABIN1 is a binding partner of mitochondria and plays a role in general housekeeping of mitochondria. ABIN1’s regulation of mitophagy is an effect of its regulation of AMP-activated protein kinase (AMPK) phosphorylation, an upstream regulator of mitophagy. Loss of ABIN1 and its disruption of mitophagy appears to influence the release of mitochondrial DNA (mtDNA) from the mitochondria. The presence of mtDNA in the cytosol presents a potential explanation for Lupus in ABIN1 mutant patients.

Library of Congress Subject Headings

Cell physiology.
Cell death.
Mitochondria.
Genetic regulation.

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Rights Statement

In Copyright