Regulation of SIRT2-dependent α-tubulin deacetylation by cellular NAD levels

Skoge, Renate Hvidsten; Dölle, Christian; Ziegler, Mathias

doi:10.1016/j.dnarep.2014.04.011

Cited by 57 publications

(56 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FK866, an inhibitor of the NAD biosynthetic enzyme NamPRT (also known as NAMPT), leads to NAD depletion in cells that rely on nicotinamide as NAD precursor. We have previously shown that FK866-induced NAD depletion results in indirect SIRT2 inactivation and gives rise to tubulin hyperacetylation (Skoge et al, 2014) (Fig. 1A).…”

Section: Inhibition Of Sirt2 Leads To the Formation Of Hyperacetylatementioning

confidence: 78%

“…3A; green and red channel, respectively). Addition of nicotinic acid restores the NAD level in FK866-treated cells and, in turn, reactivates SIRT2 (Skoge et al, 2014) (Fig. 1A).…”

Section: Hyperacetylated Perinuclear Microtubules Are Partially Resismentioning

confidence: 91%

“…Indeed, the enzymatic activity of SIRT1 has been linked to fluctuations in cellular NAD levels in several studies (Revollo et al, 2004;Fulco et al, 2008;Canto et al, 2009). Moreover, the acetylation state of α-tubulin depends on cellular NAD levels, as it is, in part, mediated by the NAD-dependent SIRT2 (Skoge et al, 2014). However, why NAD-dependent and -independent deacetylations take place on the same residues has remained unclear.…”

Section: Introductionmentioning

confidence: 99%

“…It has also been proposed that the occurrence of hyperacetylated microtubule structures during cell division, the mitotic spindle and the midbody, could be ascribed to the selective inhibition of SIRT2 by the human Furry homolog, Fry (Nagai et al, 2013). Simultaneous inhibition of SIRT2 and HDAC6 causes a stronger hyperacetylation of tubulin than achieved with either treatment alone (Skoge et al, 2014) further indicating that the two enzymes might target overlapping, but not identical microtubule populations.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

SIRT2 inactivation reveals a subset of hyperacetylated perinuclear microtubules inaccessible to HDAC6

Skoge

Ziegler

2016

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Deacetylation of α-tubulin at lysine 40 is catalyzed by two enzymes, the NAD-dependent deacetylase SIRT2 and the NAD-independent deacetylase HDAC6, in apparently redundant reactions. In the present study, we tested whether these two enzymes might have distinguishable preferences for the deacetylation of different microtubule structures. Using various agents, we induced tubulin hyperacetylation and analyzed the ensuing formation of distinct microtubule structures. HDAC6 inhibition led to general hyperacetylation of the microtubule network throughout the cell, whereas hyperacetylation induced by SIRT2 inactivation was limited to perinuclear microtubules. Hyperacetylation of these perinuclear microtubules was undiminished following HDAC6 overexpression, whereas reactivation of SIRT2 restored the basal acetylation level and a normal microtubule network. By contrast, SIRT2 and HDAC6 acted similarly on the morphologically different, hyperacetylated microtubule structures induced by taxol, MAP2c overexpression or hyperosmotic stress. These results indicate overlapping and distinct functions of HDAC6 and SIRT2. We propose that the differential activity of the two deacetylases, which target the same acetylated lysine residue, might be related to the recognition of specific structural contexts.

show abstract

Section: Inhibition Of Sirt2 Leads To the Formation Of Hyperacetylatementioning

confidence: 78%

“…3A; green and red channel, respectively). Addition of nicotinic acid restores the NAD level in FK866-treated cells and, in turn, reactivates SIRT2 (Skoge et al, 2014) (Fig. 1A).…”

Section: Hyperacetylated Perinuclear Microtubules Are Partially Resismentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SIRT2 inactivation reveals a subset of hyperacetylated perinuclear microtubules inaccessible to HDAC6

Skoge

Ziegler

2016

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…Post-translational modification, such as acetylation, is one regulator of tubulin dynamics. SIRT2 has been reported to deacetylate α-tubulin, in an NAD + dependent manner (262,263). Changes in SIRT2 activity have been linked to altered microtubule dynamics (264).…”

Section: Future Directionsmentioning

confidence: 99%

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

Hawrylyshyn¹,

Yin²,

O’Neil³

et al. 2015

Canadian Journal of Cardiology

View full text Add to dashboard Cite

show abstract

CoCl₂‐triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299

Hampel,

Georgy,

Mehrabipour

et al. 2023

FEBS Open Bio

View full text Add to dashboard Cite

SIRT4, together with SIRT3 and SIRT5, comprises the mitochondrially localized subgroup of sirtuins. SIRT4 regulates mitochondrial bioenergetics, dynamics (mitochondrial fusion), and quality control (mitophagy) via its NAD+‐dependent enzymatic activities. Here, we address the regulation of SIRT4 itself by characterizing its protein stability and degradation upon CoCl2‐induced pseudohypoxic stress that typically triggers mitophagy. Interestingly, we observed that of the mitochondrial sirtuins, only the protein levels of SIRT4 or ectopically expressed SIRT4‐eGFP decrease upon CoCl2 treatment of HEK293 cells. Co‐treatment with BafA1, an inhibitor of autophagosome–lysosome fusion required for autophagy/mitophagy, or the use of the proteasome inhibitor MG132, prevented CoCl2‐induced SIRT4 downregulation. Consistent with the proteasomal degradation of SIRT4, the lysine mutants SIRT4(K78R) and SIRT4(K299R) showed significantly reduced polyubiquitination upon CoCl2 treatment and were more resistant to pseudohypoxia‐induced degradation as compared to SIRT4. Moreover, SIRT4(K78R) and SIRT4(K299R) displayed increased basal protein stability as compared to wild‐type SIRT4 when subjected to MG132 treatment or cycloheximide (CHX) chase assays. Thus, our data indicate that stress‐induced protein degradation of SIRT4 occurs through two mechanisms: (a) via mitochondrial autophagy/mitophagy, and (b) as a separate process via proteasomal degradation within the cytoplasm.

show abstract

Regulation of SIRT2-dependent α-tubulin deacetylation by cellular NAD levels

Cited by 57 publications

References 40 publications

SIRT2 inactivation reveals a subset of hyperacetylated perinuclear microtubules inaccessible to HDAC6

SIRT2 inactivation reveals a subset of hyperacetylated perinuclear microtubules inaccessible to HDAC6

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

CoCl₂‐triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299

Contact Info

Product

Resources

About

Regulation of SIRT2-dependent α-tubulin deacetylation by cellular NAD levels

Cited by 57 publications

References 40 publications

SIRT2 inactivation reveals a subset of hyperacetylated perinuclear microtubules inaccessible to HDAC6

SIRT2 inactivation reveals a subset of hyperacetylated perinuclear microtubules inaccessible to HDAC6

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

CoCl2‐triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299

Contact Info

Product

Resources

About

CoCl₂‐triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299