Mitochondrial chaperon TNF-receptor- associated protein 1 as a novel apoptotic regulator conferring susceptibility to Pneumocystis jirovecii pneumonia

Molecular chaperons stabilize protein folding and play a vital role in maintaining tissue homeostasis. To this intent, mitochondrial molecular chaperons may be involved in the regulation of oxidative phosphorylation and apoptosis during stress events such as infections. However, specific human infec...

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Published inFrontiers in immunology Vol. 15; p. 1423086
Main Authors Amali, Aseervatham Anusha, Paramasivam, Kathirvel, Huang, Chiung Hui, Joshi, Abhinav, Hirpara, Jayshree L, Ravikumar, Sharada, Sam, Qi Hui, Tan, Rachel Ying Min, Tan, Zhaohong, Kumar, Dilip, Neckers, Leonard M, Pervaiz, Shazib, Foo, Roger, Chan, Candice Y Y, Zhu, Jin, Lee, Cheryl, Chai, Louis Yi Ann
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 19.08.2024
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Summary:Molecular chaperons stabilize protein folding and play a vital role in maintaining tissue homeostasis. To this intent, mitochondrial molecular chaperons may be involved in the regulation of oxidative phosphorylation and apoptosis during stress events such as infections. However, specific human infectious diseases relatable to defects in molecular chaperons have yet to be identified. To this end, we performed whole exome sequencing and functional immune assessment in a previously healthy Asian female, who experienced severe respiratory failure due to and non-HIV-related CD4 lymphocytopenia. This revealed that a chaperon, the mitochondrial paralog of HSP90, TRAP1, may have been involved in the patient's susceptibility to an opportunistic infection. Two rare heterozygous variants in TRAP1, E93Q, and A64T were detected. The patient's peripheral blood mononuclear cells displayed diminished TRAP1 expression, but had increased active, cleaved caspase-3, caspase-7, and elevated IL-1β production. Transfection of A64T and E93Q variants in cell lines yielded decreased TRAP1 compared to transfected wildtype and re-capitulated the immunotypic phenotype of enhanced caspase-3 and caspase-7 activity. When infected with live , the E93Q or A64T TRAP1 mutant expressing cells also exhibited reduced viability. Patient cells and cell lines transfected with the TRAP1 E93Q/A64T mutants had impaired respiration, glycolysis, and increased ROS production. Of note, co-expression of E93Q/A64T double mutants caused more functional aberration than either mutant singly. Taken together, our study uncovered a previously unrecognized role of TRAP1 in CD4 lymphocytopenia, conferring susceptibility to opportunistic infections.
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Edited by: Bart Tummers, King’s College London, United Kingdom
Hai Zhao, Qingdao University, China
Reviewed by: Danielle Oliveira Nascimento, Federal Rural University of Rio de Janeiro, Brazil
These authors have contributed equally to this work
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2024.1423086