Mitochondrial ribosomal stress in lung diseases

Mitochondria are involved in a variety of critical cellular functions, and their impairment drives cell injury. The mitochondrial ribosome (mitoribosome) is responsible for the protein synthesis of mitochondrial DNA encoded genes. These proteins are involved in oxidative phosphorylation, respiration, and ATP production required in the cell. Mitoribosome components originate from both mitochondrial and nuclear genomes. Their dysfunction can be caused by impaired mitochondrial protein synthesis or mitoribosome misassembly, leading to a decline in mitochondrial translation. This decrease can trigger mitochondrial ribosomal stress and contribute to pulmonary cell injury, death, and diseases. This review focuses on the contribution of the impaired mitoribosome structural components and function to respiratory disease pathophysiology. We present recent findings in the fields of lung cancer, chronic obstructive pulmonary disease, interstitial lung disease, and asthma. We also include reports on the mitoribosome dysfunction in pulmonary hypertension, high altitude pulmonary edema, bacterial and viral infections. Studies of the mitoribosome alterations in respiratory diseases can lead to novel therapeutic targets.

Symptom Severity, Infection Progression and Plant Responses in Solanum Plants Caused by Three Pospiviroids Vary with the Inoculation Procedure

Infectious viroid clones consist of dimeric cDNAs used to generate transcripts which mimic the longer-than-unit replication intermediates. These transcripts can be either generated in vitro or produced in vivo by agro-inoculation. We have designed a new plasmid, which allows both inoculation methods, and we have compared them by infecting Solanum lycopersicum and Solanum melongena with clones of Citrus exocortis virod (CEVd), Tomato chlorotic dwarf viroid (TCDVd), and Potato spindle tuber viroid (PSTVd). Our results showed more uniform and severe symptoms in agro-inoculated plants. Viroid accumulation and the proportion of circular and linear forms were different depending on the host and the inoculation method and did not correlate with the symptoms, which correlated with an increase in PR1 induction, accumulation of the defensive signal molecules salicylic (SA) and gentisic (GA) acids, and ribosomal stress in tomato plants. The alteration in ribosome biogenesis was evidenced by both the upregulation of the tomato ribosomal stress marker SlNAC082 and the impairment in 18S rRNA processing, pointing out ribosomal stress as a novel signature of the pathogenesis of nuclear-replicating viroids. In conclusion, this updated binary vector has turned out to be an efficient and reproducible method that will facilitate the studies of viroid–host interactions.

Mucosal ribosomal stress-induced PRDM1 promotes chemoresistance via stemness regulation

The majorities of colorectal cancer (CRC) cases are sporadic in origin and a large proportion of etiologies are associated with environmental stress responses. In response to external and internal stress, the ribosome stands sentinel and stress-driven ribosomal dysfunction triggers the cellular decision pathways via transcriptional reprogramming. In the present study, PR domain zinc finger protein (PRDM) 1, a master transcriptional regulator, was found to be closely associated with ribosomal actions in patients with CRC and the murine models. Stress-driven ribosomal dysfunction enhanced PRDM1 levels in intestinal cancer cells, which contributed to their survival and enhanced cancer cell stemness against cancer treatment. Mechanistically, PRDM1 facilitated clustering modulation of insulin-like growth factor (IGF) receptor-associated genes, which supported cancer cell growth and stemness-linked features. Ribosomal dysfunction-responsive PRDM1 facilitated signaling remodeling for the survival of tumor progenitors, providing compelling evidence for the progression of sporadic CRC.

Treatable metabolic and inflammatory abnormalities in Post COVID Syndrome (PCS) define the transcriptomic basis for persistent symptoms: Lessons from CIRS

Within three months of the onset of acute SARS-CoV-2 (COVID-19) infections, new and persistent symptoms were noted in survivors. While the world’s medical and research communities focus on saving lives following COVID-19 infection, a relentless march of new cases of Post-COVID Syndrome (PCS) continues to spread around the globe as a second COVID-related pandemic. Efforts to define the physiology of PCS, a multisystem, multi-symptom illness, continue without success, in part due to the markedly different case presentations. Using a transcriptomic assessment of persistently ill cases of PCS, we show the presence of (i) molecular hypometabolism (MHM) and proliferative physiology; (ii) elevated levels of ribosomal stress responses and a concomitant increase in gene activation of TGFBR; and (iii) common co-expression of CD14 and Toll Receptor 4, correlated to exposure of amplified microbial growth in a water-damaged environment, specifically Actinobacteria and endotoxin, respectively, compared to recovered PCS cases. Total symptom scores and visual contrast sensitivity (VCS) results showed statistically significant differences. The data reported here supports the concept that PCS occurs in patients with additional environmental exposures and enhanced TGF signaling. In a strikingly similar condition called Chronic Inflammatory Response Syndrome (CIRS), named in 2010, the transcriptomic abnormalities were identified to respond to treatment with FDA-cleared medications, with salutary benefits for affected cases. Though sparsely reported, PCS cases share proteomic findings with CIRS. While additional studies are indicated, a new approach to the treatment of PCS is suggested.

Ethylene is Involved in Symptom Development and Ribosomal Stress of Tomato Plants upon Citrus Exocortis Viroid Infection

Citrus exocortis viroid (CEVd) is known to cause different symptoms in citrus trees, and its mechanism of infection has been studied in tomato as an experimental host, producing ribosomal stress on these plants. Some of the symptoms caused by CEVd in tomato plants resemble those produced by the phytohormone ethylene. The present study is focused on elucidating the relationship between CEVd infection and ethylene on disease development. To this purpose, the ethylene insensitive Never ripe (Nr) tomato mutants were infected with CEVd, and several aspects such as susceptibility to infection, defensive response, ethylene biosynthesis and ribosomal stress were studied. Phenotypic characterization revealed higher susceptibility to CEVd in these mutants, which correlated with higher expression levels of both defense and ethylene biosynthesis genes, as well as the ribosomal stress marker SlNAC082. In addition, Northern blotting revealed compromised ribosome biogenesis in all CEVd infected plants, particularly in Nr mutants. Our results indicate a higher ethylene biosynthesis in Nr mutants and suggest an important role of this phytohormone in disease development and ribosomal stress caused by viroid infection.

USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2

p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) functions as an important regulator of p53. We show that ubiquitinated ribosomal protein S2 (RPS2) by Mouse double minute 2 homolog (MDM2) is deubiquitinated by USP47. USP47 inhibits the interaction between RPS2 and MDM2 thereby alleviating RPS2-mediated suppression of MDM2 under normal conditions. However, dissociation of USP47 leads to RPS2 binding to MDM2, which is required for the suppression of MDM2, consequently inducing up-regulation of the p53 level under ribosomal stress. Finally, we show that depletion of USP47 induces p53 and therefore inhibits cell proliferation, colony formation, and tumor progression in cancer cell lines and a mouse xenograft model. These findings suggest that USP47 could be a potential therapeutic target for cancer.