The trypanosome lytic factor receptor is required for heme-dependent sterol and fatty acid metabolism in African trypanosomes

LECORDIER, LAURENCE; ALLOATTI, ANDRÉS; UTTARO, ANTONIO; VANHOLLEBEKE, BENOIT

Newport, Rhode Island

Conferencia; Gordon Research Conferences-Biology of Host-Parasite Interactions; 2012

Gordon Research Conferences

The haptoglobin-hemoglobin receptor (HpHbR) plays a key role in human innate immunity against African trypanosomes by engaging a subset of the trypanolytic particles of human serum. The function of this receptor in non-trypanolytic host was proposed to be heme uptake but direct evidence for hemoprotein activity in the bloodstream forms and its dependency on the receptor was lacking. We gained genetic and biochemical evidence that endogenous sterol biosynthesis in the bloodstream forms relies on CYP51, an enzyme of the cytochrome P450 superfamily that catalyzes the three step oxidative 14-alpha demethylation in newly cyclized sterols. HPLC and GC-coupled mass spectrometry revealed that CYP51 activity was strictly dependent on the haptoglobin-hemoglobin uptake pathway. Similarly, cytochrome b5 dependent fatty acid desaturase reactions were altered in the absence of HpHbR. Together, these data indicate that HpHbR is required for heme-based metabolism. The absence of heme-based metabolism in cells devoid of TbHpHbR provides a rare example of an organism capable of cellular respiration in the absence of heme, as recently shown for Phytomonas.