The Substrate Specificity of Sirtuins Bheda, Poonam; Jing, Hui; Wolberger, Cynthia ...
Annual review of biochemistry,
06/2016, Letnik:
85, Številka:
1
Journal Article
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Sirtuins are NAD
+
-dependent enzymes universally present in all organisms, where they play central roles in regulating numerous biological processes. Although early studies showed that sirtuins ...deacetylated lysines in a reaction that consumes NAD
+
, more recent studies have revealed that these enzymes can remove a variety of acyl-lysine modifications. The specificities for varied acyl modifications may thus underlie the distinct roles of the different sirtuins within a given organism. This review summarizes the structure, chemistry, and substrate specificity of sirtuins with a focus on how different sirtuins recognize distinct substrates and thus carry out specific functions.
Protein lipidation, including cysteine prenylation, N-terminal glycine myristoylation, cysteine palmitoylation, and serine and lysine fatty acylation, occurs in many proteins in eukaryotic cells and ...regulates numerous biological pathways, such as membrane trafficking, protein secretion, signal transduction, and apoptosis. We provide a comprehensive review of protein lipidation, including descriptions of proteins known to be modified and the functions of the modifications, the enzymes that control them, and the tools and technologies developed to study them. We also highlight key questions about protein lipidation that remain to be answered, the challenges associated with answering such questions, and possible solutions to overcome these challenges.
Sirtuins use NAD
+
to remove various acyl groups from protein lysine residues. Through working on different substrate proteins, they display many biological functions, including regulation of cell ...proliferation, genome stability, metabolism, and cell migration. There are seven sirtuins in humans, SIRT1-7, each with unique enzymatic activities, regulatory mechanisms, subcellular localizations, and substrate scopes. They have been indicated in many human diseases, including cancer, neurodegeneration, microbial infection, metabolic and autoimmune diseases. Consequently, interests in development of sirtuin modulators have increased in the past decade. In this brief review, we specifically summarize genetic and pharmacological modulations of sirtuins in cancer, neurological, and cardiovascular diseases. We further anticipate this review will be helpful for scrutinizing the significance of sirtuins in the studied diseases.
Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein ...thioesterases1,2. Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (TH17) cell differentiation stimulator, STAT33,4, is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation-depalmitoylation cycle enhances STAT3 activation and promotes TH17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects TH17 cell differentiation. Overactivation of TH17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout ofZdhhc7-which encodes DHHC7-relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events.
The smallest histone deacetylase (HDAC) and the only class IV HDAC member, HDAC11, is reported to regulate immune activation and tumorigenesis, yet its biochemical function is largely unknown. Here ...we identify HDAC11 as an efficient lysine defattyacylase that is >10,000-fold more efficient than its deacetylase activity. Through proteomics studies, we hypothesized and later biochemically validated SHMT2 as a defatty-acylation substrate of HDAC11. HDAC11-catalyzed defatty-acylation did not affect the enzymatic activity of SHMT2. Instead, it affects the ability of SHMT2 to regulate type I IFN receptor ubiquitination and cell surface level. Correspondingly, HDAC11 depletion increased type I IFN signaling in both cell culture and mice. This study not only demonstrates that HDAC11 has an activity that is much more efficient than the corresponding deacetylase activity, but also expands the physiological functions of HDAC11 and protein lysine fatty acylation, which opens up opportunities to develop HDAC11-specific inhibitors as therapeutics to modulate immune responses.
In the past few years, several new protein post-translational modifications that use intermediates in metabolism have been discovered. These include various acyl lysine modifications (formylation, ...propionylation, butyrylation, crotonylation, malonylation, succinylation, myristoylation) and cysteine succination. Here, we review the discovery and the current understanding of these modifications. Several of these modifications are regulated by the deacylases, sirtuins, which use nicotinamide adenine dinucleotide (NAD), an important metabolic small molecule. Interestingly, several of these modifications in turn regulate the activity of metabolic enzymes. These new modifications reveal interesting connections between metabolism and protein post-translational modifications and raise many questions for future investigations.
Our genome encodes about 20,000 genes, which are transcribed into mRNA and then translated into proteins. Proteins perform numerous biochemical functions and are central for all life processes, ...including metabolism, signal transduction, transcription, translation, cellular structural integrity, and cell movement. A common feature of all living organisms is the ability to adapt to and survive the changing environment. In order to respond to environmental changes, the proteins of a living organism, or the proteome, must change. New proteins may need to be synthesized to deal with an environmental stress. At the same time, existing proteins can undergo certain chemical modifications, commonly referred to as protein post-translational modifications (PTMs), which introduce structural changes in proteins and thus produce signal responses.
Polyadenosine diphosphate (ADP)—ribose polymerases (PARPs) are a family of enzymes that modulate diverse biological processes through covalent transfer of ADP-ribose from the oxidized form of ...nicotinamide adenine dinucleotide (NAD⁺) onto substrate proteins. Here we report a robust NAD⁺ analog—sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent coppercatalyzed azide-alkyne cycloaddition reactions. Using this approach, we mapped hundreds of sites of ADP-ribosylation for PARPs 1, 2, and 3 across the proteome, as well as thousands of PARP-1—mediated ADP-ribosylation sites across the genome. We found that PARP-1 ADP-ribosylates and inhibits negative elongation factor (NELF), a protein complex that regulates promoter-proximal pausing by RNA polymerase II (Pol II). Depletion or inhibition of PARP-1 or mutation of the ADP-ribosylation sites on NELF-E promotes Pol II pausing, providing a clear functional link between PARP-1, ADP-ribosylation, and NELF. This analog-sensitive approach should be broadly applicable across the PARP family and has the potential to illuminate the ADP-ribosylated proteome and the molecular mechanisms used by individual PARPs to mediate their responses to cellular signals.
Protein cysteine palmitoylation, or S‐palmitoylation, has been known for about 40 years, and thousands of proteins in humans are known to be modified. Because of the large number of proteins ...modified, the importance and physiological functions of S‐palmitoylation are enormous. However, most of the known physiological functions of S‐palmitoylation can be broadly classified into two categories, neurological or immunological. This review provides a summary on the function of S‐palmitoylation from the immunological perspective. Several important immune signaling pathways are discussed, including STING, NOD1/2, JAK‐STAT in cytokine signaling, T‐cell receptor signaling, chemotactic GPCR signaling, apoptosis, phagocytosis, and endothelial and epithelial integrity. This review is not meant to be comprehensive, but rather focuses on specific examples to highlight the versatility of palmitoylation in regulating immune signaling, as well as the potential and challenges of targeting palmitoylation to treat immune diseases.
Protein cysteine palmitoylation, catalyzed by ZDHHC type palmitoyltransferases, regulates numerous immune signaling pathways. Targeting palmitoylation is therefore a promising strategy for treating inflammation and autoimmune diseases.
The NAD+-dependent deacetylase Sirtuin 1 (SIRT1) is down-regulated in triple-negative breast cancer. To determine the mechanistic basis by which reduced SIRT1 expression influences processes related ...to certain aggressive cancers, we examined the consequences of depleting breast cancer cells of SIRT1. We discovered that reducing SIRT1 levels decreased the expression of one particular subunit of the vacuolar-type H+ ATPase (V-ATPase), which is responsible for proper lysosomal acidification and protein degradation. This impairment in lysosomal function caused a reduction in the number of multi-vesicular bodies (MVBs) targeted for lysosomal degradation and resulted in larger MVBs prior to their fusing with the plasma membrane to release their contents. Collectively, these findings help explain how reduced SIRT1 expression, by disrupting lysosomal function and generating a secretome comprising exosomes with unique cargo and soluble hydrolases that degrade the extracellular matrix, can promote processes that increase breast-cancer-cell survival and invasion.
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•SIRT1 expression is frequently decreased in aggressive breast cancers•Reducing SIRT1 levels in breast cancer cells impairs lysosomal acidification•Loss of SIRT1 gives rise to a secretome that promotes cell invasion and survival•SIRT1 mediates these effects by regulating V-ATPase expression
Sirtuin 1 (SIRT1) expression is down-regulated in triple-negative breast cancer. Latifkar et al. show how reducing SIRT1 levels inhibit proper lysosomal function and, in doing so, results in the generation of a secretome with unique components, i.e., exosomes and resident lysosomal hydrolases, that promote the aggressiveness of breast cancer cells.
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