Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

Abstract

The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD + -dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.neuropathy | sirtuin | acetylation M yelinating Schwann cells (SCs) perform a range of tasks required for correct function of the peripheral nervous system (PNS). In addition to ensuring normal locomotion and sensation and providing trophic support of axons (1), they control regenerative and reparative responses in peripheral nerves (2). These functions are tightly linked to the ability of differentiated SCs to intimately associate with axons and ensheath them with compact myelin. Various pathways in SCs have been identified that are crucial for this process including neuronal growth factors, cell adhesion, and a number of second messenger systems (3). These pathways are interrelated with strict temporal control of key transcription factors, collectively responsible for up-regulation of genes critical for structural assembly of myelin (3, 4).Metabolic derangements contribute to a major class of conditions in which SC function is impaired. For example, numerous studies indicate that nerve regeneration and myelination after injury are impaired in diabetic neuropathy (5-8). Moreover, SC myelination can be altered by changes in nutrition (9, 10). These findings give rise to the idea that abnormal metabolic conditions could lead to aberrant myelination via abnormalities in SC function. We previously identified Sir-two-homolog 2 (Sirt2) in gene expression profiling experiments as a putative myelinationassociated protein on the basis of the similarity of its expression to that of mRNAs encoding structural myelin proteins during periods of myelin formation (11). Sirt2 is a member of the conserved sirtuin family of NAD + -dependent deacetylases that modulate cellular processes in accord with the metabolic state (12, 13). Depending on the cellular context and tissue type, Sirt2 is reported to deacetylate α-tubulin (14, 15), control cell division (16), regulate adipocyte differentiation through FOXO1 (17), and alter gene expression via the deacetylation of histone H4 (18) among other functions.Here, we demonstrate that norm...

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“…This role in particular is believed to promote longevity in yeast. In line with this hypothesis, extra copies of Sir2 increase yeast life span whereas deletion of Sir2 has the opposite effect [22,23].…”

“…Since deletion of the NES led to nucleocytoplasmic distribution, it was suggested to mediate their cytosolic localization [21]. Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system and gluconeogenesis [15,[22][23][24]. There is growing evidence for additional functions of SIRT2 in the nucleus.…”

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“…Moreover, a recent finding suggests that SIRT2 is activating myelin formation in Schwann cells, thus controlling an essential polarity pathway during myelin assembly (25). The effects of exercise on SIRT2 are generally unknown.…”

Propofol Inhibits SIRT2 Deacetylase through a Conformation-specific, Allosteric Site

“…However, although we used acetylated ␣-tubulin as a model substrate in our assays, there are numerous other proteins and cellular processes that are regulated by SIRT2. For example, as a major deacetylase in oligodendrocytes (39 -41), SIRT2 activity regulates the development of myelin and also remyelination of axons after crush injury (42). In other cell types, SIRT2 deacetylates transcription factors (43) and histones (44,45) to regulate transcription and chromatin structure, and SIRT2 regulates metabolic enzyme function (46).…”