Biology subjects

Jae, L. T.

Publications and source records attributed to Jae, L. T..

3 recordsLinked to original sources

bioRxiv2025

The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness

The mitochondrial disulphide relay is the key machinery for import and oxidative protein folding in the mitochondrial intermembrane space. Among IMS proteins with unknown function, we identified FAM136A as a new substrate of the mitochondrial disulphide relay. We demonstrate a transient interaction between FAM136A and MIA40, and that MIA40 introduces four disulphide bonds in two twin-CX3C motifs of FAM136A. Consequently, IMS import of FAM136A requires these cysteines and its steady state levels in intact cells are strongly dependent on MIA40 and AIFM1 levels. Furthermore, we show that FAM136A forms non-covalent homodimers as a mature protein. Acute deletion of FAM136A curtails cellular proliferation capacity and elicits a robust induction of the integrated stress response, coincident with the aggregation and/or depletion of selected IMS proteins including HAX1 and CLPB. Together, this establishes FAM136A as a pivotal component of the IMS proteostasis network, with implications for overall cellular function and health.

biochemistry↗

bioRxiv2025

AMPylation regulates PLD3 processing.

The 5-3 exonuclease phospholipase D3 (PLD3) is a single-pass transmembrane protein undergoing sequential post-translational modifications (PTM) by N-glycosylation, AMPylation and proteolytic cleavage. The substrates of PLD3 5-3 exonuclease activity are single-stranded DNAs and RNAs, which act as ligands for Toll-like receptors (TLRs) and trigger a downstream pro-inflammatory response. Although PLD3 has primarily been studied in immune cells, recent findings indicate its enrichment in neurons, where it plays a role in regulating axonal fitness in Alzheimers disease (AD). However, the regulatory mechanisms governing the proteolytic processing of PLD3 into its catalytically active soluble form and its functional roles in both immune and neuronal cells remain unclear. Here, we describe the functional implications of PLD3 AMPylation, its direct interaction with the protein adenylyltransferase FICD, and changes in PLD3 processing in Parkinsons disease (PD) patient-derived neurons. We identified PLD3 AMPylation sites within the proteins soluble region and show that mutation of these sites lead to loss of PLD3 exonuclease catalytic activity. FICD AMP-transferase accelerates PLD3 degradation and induces cellular stress response. Furthermore, depletion of the two human AMP-transferases FICD and SelO point towards a complex regulatory network governing PLD3 AMPylation. Together, our findings demonstrate a critical role of AMPylation in PLD3 processing and regulation of its catalytic activity and provide new insights into the proteins transport and localization to lysosomes. The observation that PLD3 regulation in PD-derived neurons is altered compared to healthy neurons further highlights its role in neurodegenerative diseases.

biochemistry↗

bioRxiv2022

A mitochondrial iron-sensing pathway regulated by DELE1

The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron deficiency-induced HRI activation involves a heme-independent mechanism that requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Moreover, depletion of the mitochondrial ABC transporter ABCB7 that is involved in iron-sulfur cluster (ISC) metabolism markedly abrogates iron deficiency-induced ISR activation, suggesting the possible involvement of ISC-related molecules in this activation. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized iron monitoring system that connects the mitochondria to the cytosol.

cell biology↗