Chlamydia trachomatis plasmid-encoded protein pORF5 protects mitochondrial function by inducing mitophagy and increasing HMGB1 expression

Abstract

Chlamydia trachomatis, an obligate intracellular pathogen, has various effective strategies to regulate host cell death signalling pathways that ensure completion of their growth cycle. Mitochondrial autophagy (mitophagy) is responsible for elimination of dysfunctional and impaired mitochondria, and this process plays a critical role in cell survival via restriction of the mitochondrial apoptotic pathway. However, the specific molecular mechanisms are not entirely understood. In the present study, we observed that pORF5 plasmid protein of C. trachomatis plays a crucial role in attenuating mitochondrial dysfunction and apoptosis. Knockdown high mobility group box 1 (HMGB1) by lentivirus suppressed pORF5-induced mitophagy and increased apoptosis, implying that pORF5 may participate in cell death signalling pathways via up-regulation of HMGB1. Thus, we concluded that up-regulation of HMGB1 is a pivotal event for C. trachomatis that manipulates mitophagy and apoptosis in order to establish a favourable environment supportive of Chlamydial growth, which should further promote our understanding of Chlamydial pathogenic mechanisms.

Chlamydia trachomatis Plasmid Protein pORF5 Up-Regulates ZFAS1 to Promote Host Cell Survival via MAPK/p38 Pathway

“…Examples include activating transcription factor 1, 2, and 6 (ATF-1/2/6), p53, MITF1, DDIT3, ELK1, and high mobility group-box protein 1 (HMGB1) and so on (Zarubin and Han, 2005). Consistent with the changes of these transcription factors, pORF5 protein was proved to be able to up-regulate DDIT3, activate the expression of unfolded protein and its downstream molecules ATF4, ATF6, and CHOP, thereby promoting cell autophagy (Wen et al, 2020), and also up-regulate the expression of HMGB1 and induce mitochondrial autophagy to resist apoptosis (Lei et al, 2017). MAPK pathway deeply influences the cellular physiological processes, and can active by pORF5 secreted by C. trachomatis.…”

“…Our previous studies also verified that pORF5 influenced the expression of host proteins (Zou et al, 2018). These alternated proteins take part in cellular processes including apoptosis and autophagy (Lei et al, 2017), indicating that pORF5 plays a key role in the pathogenesis of C. trachomatis.…”

Chlamydia trachomatis induces lncRNA MIAT upregulation to regulate mitochondria‐mediated host cell apoptosis and chlamydial development

“…[47][48][49] Currently, it is believed that C. trachomatis can proliferate itself by resisting host cell apoptosis, and some studies have also shown that the enlargement of Chlamydia inclusions would promote cell apoptosis. 50 In this study, we combined our previous work 51,52 to propose the scientific hypothesis that persistent C. trachomatis infection-related differential lncRNAs might be involved in host cell antiapoptotic activity. Subsequently, we used a microarray platform to perform transcriptome analysis of lncRNAs and protein-coding genes in an in-vitro cell model of persistent C. trachomatis infection.…”

“…In this study, we combined our previous work 51 , 52 to propose the scientific hypothesis that persistent C . trachomatis infection‐related differential lncRNAs might be involved in host cell antiapoptotic activity.…”

<p>Bacteria Exploit Autophagy For Their Own Benefit</p>

“…Moreover, Lei et al demonstrated that C. trachnomatis plasmid-encoded protein pORF5 up-regulated the expression of high mobility group box 1 (HMGB1) which induces mitophagy and inhibits apoptosis of host cells (Table 1, Figure 1). 47 These findings suggest that C. trachnomatis could manipulate host cell death to usurp enough nutrients generated via autophagy for their survival and replication.…”