Mycobacterial protein PE_PGRS30 induces macrophage apoptosis through prohibitin 2 mitochondrial function interference

Kazunori Matsumura; Satoshi Takaki; Teruo Kirikae

doi:10.3389/fmicb.2023.1080369

Mycobacterial protein PE_PGRS30 induces macrophage apoptosis through prohibitin 2 mitochondrial function interference

Front Microbiol. 2023 Jan 27:14:1080369. doi: 10.3389/fmicb.2023.1080369. eCollection 2023.

Authors

Kazunori Matsumura¹, Satoshi Takaki¹, Teruo Kirikae²

Affiliations

¹ Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
² Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Abstract

PE_PGRS30 belongs to the PE_PGRS protein family and is characterized by a conserved Pro-Glu (PE) domain and a typically polymorphic GC-rich sequence (PGRS) domain. PE_PGRS30 is a virulence factor of Mycobacterium tuberculosis that induces macrophage cell death. We found that RAW264.7 cells and murine alveolar macrophages underwent apoptosis in response to PE_PGRS30. The host protein prohibitin 2 (PHB2) was identified as a target molecule. PE_PGRS30 and PHB2 interact via the PGRS domain and mitochondrial targeting sequence, respectively. PHB2 overexpression reduced macrophage apoptosis in response to PE_PGRS30. PE_PGRS30 co-localized with PHB2, not in mitochondria, but in lysosomes. The maintenance of mitochondrial structure by PHB2 was impaired in response to the PGRS domain. These results indicated that PE_PGRS30 reduces PHB2 in mitochondria, resulting in mitochondrial dysfunction and cellular apoptosis.

Keywords: PE_PGRS30; PHB2; apoptosis; macrophages; mitochondria; tuberculosis.