Sirtuin 5 Deficiency Does Not Compromise Innate Immune Responses to Bacterial Infections

Abstract

Sirtuin 5 (SIRT5) is a member of the family of NAD+-dependent lysine/histone deacetylases. SIRT5 resides mainly in the mitochondria where it catalyzes deacetylation, demalonylation, desuccinylation, and deglutarylation of lysine to regulate metabolic and oxidative stress response pathways. Pharmacologic inhibitors of SIRT5 are under development for oncologic conditions, but nothing is known about the impact of SIRT5 on antimicrobial innate immune defenses. Using SIRT5 knockout mice, we show that SIRT5 deficiency does not affect immune cell development, cytokine production and proliferation by macrophages and splenocytes exposed to microbial and immunological stimuli. Moreover, preclinical models suggest that SIRT5 deficiency does not worsen endotoxemia, Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, Escherichia coli peritonitis, listeriosis, and staphylococcal infection. Altogether, these data support the safety profile in terms of susceptibility to infections of SIRT5 inhibitors under development.

Impact of the Dual Deletion of the Mitochondrial Sirtuins SIRT3 and SIRT5 on Anti-microbial Host Defenses

“…The extracellular acidification rate (ECAR), a readout of the glycolytic activity, was not affected in resting and LPS stimulated SIRT3/5 −/− BMDMs (Figure 1I and Supplementary Figure S3A). OCR and ECAR were similarly affected in resting SIRT3 −/− BMDMs (Supplementary Figure S3B) and SIRT5 −/− BMDMs (38). The dependency, capacity, and flexibility of BMDMs to oxidize the mitochondrial fuels glucose, glutamine and fatty acids were identical for SIRT3/5 +/+ and SIRT3/5 −/− BMDMs (Figure 1J).…”

“…Macrophages and neutrophils are proficient at sensing microbial products and play key defense roles during infections. SIRT3 and SIRT5 single deficiency did not influence antimicrobial host defenses (37, 38). Therefore, we asked whether dual deficiency of SIRT3 and SIRT5 would reveal a phenotype unseen in single knockouts.…”

“…Overall, targeting the activity of sirtuins and particularly mitochondrial sirtuins is viewed as an attractive therapeutic strategy to tackle the development of age-related disorders (10, 28–30). Considering that inflammation is an essential component of innate immune defenses, we analyzed the impact of SIRT3 and SIRT5 deficiencies on the response of mice subjected to a broad panel of preclinical models of bacterial and fungal sepsis (37, 38). Neither SIRT3 nor SIRT5 was critical to fight against infections.…”

SIRT5 impairs aggregation and activation of the signaling adaptor MAVS through catalyzing lysine desuccinylation

“…Whether the enzyme responsible for succinylation existed is still debatable, but SIRT5 has been identified as an important desuccinylase, which plays pivotal functions in diverse pathways (Park et al, 2013;Rardin et al, 2013;Anderson et al, 2014;Wang et al, 2017a;Heinonen et al, 2018). However, to date, the connection between protein desuccinylation catalyzed by SIRT5 and RLR-mediated innate immune activation has remained elusive.…”

SIRT5 is important for bacterial infection by regulating insulin secretion and glucose homeostasis

“…We appreciate that Heinon et al have recently reported that Sirt5 deficiency does not compromise the response to bacterial infection (Heinonen et al, 2018). We used different background mice and bacterial strains from them.…”