Phosphorylation regulates mycobacterial proteasome

Abstract

Mycobacterium tuberculosis possesses a proteasome system that is required for the microbe to resist elimination by the host immune system. Despite the importance of the proteasome in the pathogenesis of tuberculosis, the molecular mechanisms by which proteasome activity is controlled remain largely unknown. Here, we demonstrate that the α-subunit (PrcA) of the M. tuberculosis proteasome is phosphorylated by the PknB kinase at three threonine residues (T84, T202, and T178) in a sequential manner. Furthermore, the proteasome with phosphorylated PrcA enhances the degradation of Ino1, a known proteasomal substrate, suggesting that PknB regulates the proteolytic activity of the proteasome. Previous studies showed that depletion of the proteasome and the proteasome-associated proteins decreases resistance to reactive nitrogen intermediates (RNIs) but increases resistance to hydrogen peroxide (H2O2). Here we show that PknA phosphorylation of unprocessed proteasome β-subunit (pre-PrcB) and α-subunit reduces the assembly of the proteasome complex and thereby enhances the mycobacterial resistance to H2O2 and that H2O2 stress diminishes the formation of the proteasome complex in a PknA-dependent manner. These findings indicate that phosphorylation of the M. tuberculosis proteasome not only modulates proteolytic activity of the proteasome, but also affects the proteasome complex formation contributing to the survival of M. tuberculosis under oxidative stress conditions.

Precise assembly and regulation of 26S proteasome and correlation between proteasome dysfunction and neurodegenerative diseases

“…For example, several subunits of the 20S CP are known to be phosphorylated. Phosphorylation of the α-subunit in the Mycobacterium tuberculosis proteasome impedes assembly of the proteasome complex and consequently enhances mycobacterial resistance to H 2 O 2 (50). PKA phosphorylates several subunits of the mammalian 20S CP, including α1-α3, β2, β3 and β7, thus increasing the proteasomal chymotryptic and PGPH activities (51).…”

Local suppression and enhancement of the pairing condensate under rotation

“…As the name indicates, this phenomenon shall be a generic one which has also been observed in cold atom systems [39]. This phenomenon is driven by the "force" along the radial direction which could be explicit derived in the Heisenberg equation [43]. In such a slowly rotating system, technically the condensate profile is supposed to be mainly induced by the ∂ω/∂r.…”

Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity

“…Moreover, β1, the variant identified in this current study, has been reported to promote anti-apoptotic activity of plasminogen activator inhibitor 2 (PAI2) [75]. While the consequences of the phosphorylation of this subunit are unclear, it has been shown that phosphorylation of β-subunits in the prokaryote M. tuberculosis can inhibit proteasomal assembly [76]. While there are multiple β-subunits in eukaryotes, unlike in prokaryotes that have only one type, the reduced phosphorylated states in the oldest NMR brains could suggest that there is an increased affinity towards proteome assembly and therefore, an increased degradation of unwanted or damaged proteins, clearing the cell of detritus to promote healthy cellular function.…”