PDZD8

Prognostic stratification of patients with sepsis is important for the development of individualized treatment strategies. Endoplasmic reticulum stress (ERS) plays a key role in sepsis. This study aimed to identify a set of genes related to ER stress to construct a predictive model for the prognosis of sepsis.

The transcriptomic and clinical data of 479 sepsis patients were obtained from GSE65682 and divided into a training set (n=288) and a validation set (n=191) at a ratio of 3:2. The external test set was GSE95233 (n=51). LASSO and Cox regression analyses were performed to establish a signature to predict the prognosis of patients with sepsis. Moreover, we developed a nomogram that included the risk signature and clinical features to predict survival probability.

A prognostic signature was constructed with ten endoplasmic reticulum related genes (ADRB2, DHCR7, GABARAPL2, MAOA, MPO, PDZD8, QDPR, SCAP, TFRC, and TLR4) in the training set, which significantly divided patients with sepsis into high- and low-risk groups in terms of survival. This signature was validated using validation and external test sets. A nomogram based on the risk signature was constructed to quantitatively predict the prognosis of patients with sepsis.

We constructed an ERS signature as a novel prognostic marker for predicting survival in sepsis patients, which could be used to develop novel biomarkers for the diagnosis, treatment, and prognosis of sepsis and to provide new ideas and prospects for future clinical research.

Building synaptic connections, which are often far from the soma, requires coordinating a host of cellular activities from transcription to protein turnover, placing a high demand on intracellular communication. Membrane contact sites (MCSs) formed between cellular organelles have emerged as key signaling hubs for coordinating an array of cellular activities. We have found that the endoplasmic reticulum (ER) MCS tethering protein PDZD8 is required for activity-dependent synaptogenesis. PDZD8 is sufficient to drive ectopic synaptic bouton formation through an autophagy-dependent mechanism and required for basal synapse formation when autophagy biogenesis is limited. PDZD8 functions at ER-late endosome/lysosome (LEL) MCSs to promote lysosome maturation and accelerate autophagic flux. Mutational analysis of PDZD8's SMP domain further suggests a role for lipid transfer at ER-LEL MCSs. We propose that PDZD8-dependent lipid transfer from ER to LELs promotes lysosome maturation to increase autophagic flux during periods of high demand, including activity-dependent synapse formation.

The deregulation of circular RNA (circRNA) is widely reported in carcinogenesis. The purpose of this study was to investigate the role of circRNA-PDZ domain containing 8 (circ-PDZD8) in non-small cell lung cancer (NSCLC) progression.

The histological structure of tissues was identified by hematoxylin-eosin (HE) staining analysis. The expression levels of circ-PDZD8, miR-330-5p and la ribonucleoprotein 1 (LARP1) mRNA were ascertained by qPCR. Cell counting kit-8, colony formation, flow cytometry, and transwell assays were employed for functional analysis. Glutamine metabolism was monitored by glutamine consumption, alpha ketoglutarate (α-KG) level and adenosine triphosphate (ATP) level. A xenograft model was established to ascertain the role of circ-PDZD8 in vivo. The putative binding relationships were verified by dual-luciferase and RIP studies.

Circ-PDZD8 expression was highly increased in NSCLC. Circ-PDZD8 knockdown inhibited cell growth, migratory capacity, invasiveness and glutamine metabolism but enhanced cell apoptosis in NSCLC cells. Circ-PDZD8 blocked miR-330-5p expression, and miR-330-5p inhibition overturned the effects of circ-PDZD8 absence. LARP1 targeted by miR-330-5p, and miR-330-5p upregulation-impaired cell growth, motility and glutamine metabolism were recovered by LARP1 overexpression. Circ-PDZD8 knockdown was also shown to impede solid tumor growth.

Circ-PDZD8 promotes NSCLC cell growth and glutamine metabolism by increasing LARP1 via competitively targeting miR-330-5p.