The Mycobacterium tuberculosis protein O-phosphorylation landscape

Abstract

Protein phosphorylation is a main mechanism for translating extracellular signals into cellular adaptations. In bacteria, the two-component system has been the paradigm of protein phosphorylation. Increasingly, however, protein serine/threonine and tyrosine phosphorylation (O-phosphorylation) mediated by serine/threonine protein kinases (STPKs) is identified. Mycobacterium tuberculosis (Mtb) in particular has a larger repertoire of both STPKs and O-phosphoproteins than most bacteria, suggesting a more prevalent role of STPKs in Mtb. Many studies have identified individual STPK functions and substrates, but a systems-level understanding and the full scope of Ophosphorylation in bacteria in general and Mtb in particular remains unknown. In this dissertation, we aimed to establish a systems-wide understanding of Mtb Ophosphorylation. To this end, we combined kinase loss-of-function (LoF) and gain-of-

Nucleotidyltransferase toxin MenT targets and extends the aminoacyl acceptor ends of serine tRNAs in vivo to control Mycobacterium tuberculosis growth

“…M. tuberculosis could dephosphorylate MenT3 in vitro (Yu et al , 2020). Reversibly, a fraction of free active MenT3 could also be affected by endogenous Ser/Thr protein kinases (STPKs) like PknD and PknF (Frando et al , 2023), suggesting that the level of active endogenous MenT3 toxin might not solely be controlled by the antitoxin, but also by responsive endogenous kinase/phosphatase networks to ensure translational control is attuned to physiological need during growth and infection.…”

Ser/Thr Phosphorylation ofMycobacterium tuberculosisType II Rel TA module by Protein Kinase K interferes with toxin neutralization: A novel mode of TA regulation

“…It is noteworthy that M. tuberculosis is equipped with distinct eukaryotic-like protein kinases (32, 33) and that TakA has very little similarity with these proteins, thus providing the rationale to investigate the role of STPKs in the regulation of TA modules. During the preparation of this manuscript, Frando et al, reported widespread O -phosphorylation of the M. tuberculosis H37Rv proteome (48). While their data implicated multiple STPKs in TA regulation, this study is the first instance that provides direct biochemical evidence of post-translational modification of mycobacterial Type II Rel TA modules via PknK highlighting a novel underlying regulatory mechanism to modulate TA function.…”

More than two components: complexities in bacterial phosphosignaling

“…Several recent studies are beginning to revise this view. The number of phosphosites identified in MS-based studies is climbing sharply, with several recent studies showing pervasive O -phosphorylation ( 14 – 22 ) ( Fig. 1 ).…”

“…1 ). In fact, in Mycobacterium tuberculosis ( Mtb ), a degree of phosphorylation that is on par with O -phosphorylation in eukaryotes has recently been identified ( 14 ) ( Fig. 1 ).…”