The AMPKα1 Pathway Positively Regulates the Developmental Transition from Proliferation to Quiescence in Trypanosoma brucei

Abstract

During infection in mammals, the protozoan parasite Trypanosoma brucei transforms from a proliferative bloodstream form to a quiescent form that is pre-adapted to host transition. AMP analogs are known to induce quiescence and also inhibit TbTOR4. To examine the role of AMP-activated kinase (AMPK) in regulation of this developmental transition, we characterized trypanosome TbAMPK complexes. Expression of a constitutively active AMPKα1 induces quiescence of the infective form and TbAMPKα1 phosphorylation occurs during differentiation of wild-type pleomorphic trypanosomes to the quiescent stumpy form in vivo. Compound C, a well-known AMPK inhibitor inhibits parasite differentiation in mice. We also provide evidence linking oxidative stress to TbAMPKα1 activation and quiescent differentiation, suggesting that TbAMPKα1 activation balances quiescence, proliferation and differentiation.

SUMOylated SNF2PH promotes variant surface glycoprotein expression in bloodstream trypanosomes

“…Bloodstream pleomorphic trypanosomes undergo differentiation from the proliferative to the quiescent stumpy form throughout mice infection. SNF2PH protein levels analysis in the pleomorphic AnTAT 90.13 strain decreased at 4-5 days postinfection (Appendix Fig S5C), whereas AMPKa1 was fully activated as previously described [42]. Taken altogether, these data suggest that SNF2PH is negatively regulated during transition to stumpy form and mechanistically linked to AMPKa1 activation by an undefined mechanism.…”

Phosphoinositide signaling and regulation in Trypanosoma brucei: Specialized functions in a protozoan pathogen

“…IPMK interacts with 5' adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) and regulates glucose and amino acid signaling [31,32]. AMPK and target of rapamycin 4 (TOR4) complexes are also involved in T. brucei metabolism and development [2,3], but it is unknown if they associate with T. brucei IPMK. Moreover, the control of energy metabolism in T. brucei depends on IPMK catalytic activity and thus on IPs [6].…”

“…They also have elaborate mechanisms of gene regulation that control the expression of genes involved in host immune evasion during infection. The control of developmental changes and immune evasion mechanisms entails a complex network of signaling and regulatory processes that includes phosphatidylinositol (PI) phosphates (PIP, also called phosphoinositides) and inositol phosphates (IP) [2][3][4][5][6][7][8]. PIPs and IPs are ubiquitous in eukaryotes and consist of a subset of molecules containing mono or poly phosphorylated inositol ( Fig 1A).…”

The Cytological Events and Molecular Control of Life Cycle Development of Trypanosoma brucei in the Mammalian Bloodstream

“…Characteristics of stumpy cells that likely contribute to their survival in the fly midgut include their relative resistance to acidic and proteolytic stress [ 14 ]. For example, the differential response to mild acid conditions (pH 5.5) has been used as a selection to monitor the differentiation to stumpy cells in some studies [ 15 ], as slender cells are sensitive and stumpy cells are resistant. Moreover, protease treatment has been shown to act as a trigger for bloodstream forms to differentiate to procyclic cells [ 16 , 17 , 18 ].…”

“…More recently, Saldivia et al [ 15 ] have suggested that AMPKα1, and not the AMPKα2 that was identified in the Mony et al screen [ 102 ], is associated with the positive regulation of stumpy form development. In vitro phosphorylation analysis using an α-phospho-Thr172 antibody showed that AMPKα1 phosphorylation was significantly upregulated upon treatment with 8-pCPTAMP, whereas AMPKα2 phosphorylation levels were unaffected.…”