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Heat Shock Protein Plays Critical Role in Malaria Parasite Protein Trafficking

By BiotechDaily International staff writers
Posted on 29 Jul 2014
Image: Blocking the activity of HSP101 may imprison the malaria parasite inside its protective vacuole within the red blood cell. In the electron micrograph, the malaria parasites appear in blue and uninfected red blood cells are shown in red (Photo courtesy of the [US] National Institute of Allergy and Infectious Diseases).
Image: Blocking the activity of HSP101 may imprison the malaria parasite inside its protective vacuole within the red blood cell. In the electron micrograph, the malaria parasites appear in blue and uninfected red blood cells are shown in red (Photo courtesy of the [US] National Institute of Allergy and Infectious Diseases).
A pair of recent papers described the molecular operators that enable the malaria parasite Plasmodium falciparum to export a large variety of proteins across the parasitophorous vacuolar membrane (PVM) within which the parasite resides into the cytoplasm of the infected red blood cell.

The mechanism by which P. falciparum exports hundreds of proteins into the host erythrocyte in order to mediate its survival and virulence has been poorly understood. Researchers on the topic have suggested the existence of a Plasmodium translocon of exported proteins (PTEX) to account for this activity. A translocon is a protein complex in the plasma membrane that governs protein secretion and membrane protein insertion. The translocon channel provides a route for proteins to pass through the hydrophobic barrier of the membrane, assisted by various partner proteins which maintain an unfolded state of the substrate, target it to the channel, and provide the energy and mechanical drive required for transport. In prokaryotes, the post-translational reaction utilizes an ATPase that couples the free energy of ATP binding and hydrolysis to move the substrate through the protein pore.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) looked at the possible involvement of the heat shock protein HSP101 in this process. Heat shock proteins (HSP) are a group of proteins induced by heat shock. The most prominent members of this group are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. By helping to stabilize partially unfolded proteins, HSPs aid in transporting proteins across membranes within the cell.

The investigators reported in the July 16, 2014, online edition of the journal Nature that inhibiting HSP101 function resulted in a nearly complete block in protein export from the parasitophorous vacuole with substrates accumulating in the vacuole in both asexual and sexual parasites. This block extended to all classes of exported proteins, revealing HSP101-dependent translocation across the PVM as a focal point in a multi-pathway export process.

In a second paper published in the same edition of Nature, investigators at Burnet Institute (Melbourne, Australia) and Deakin University (Melbourne, Australia) described experiments carried out with lines of P. falciparum that lacked the gene for HSP101 or another suggested PTEX protein, PTEX150.

The modified parasites demonstrated greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in P. falciparum, was significantly reduced in the PTEX knockdown parasites. PTEX function was also found to be essential for blood-stage growth, as even a modest knockdown of PTEX components had a strong effect on the parasite’s capacity to complete the erythrocytic cycle both in vitro and in vivo.

“We think this [PTEX] is a very promising target for drug development,” said senior author Dr. Daniel Goldberg, professor of medicine and molecular microbiology at Washington University School of Medicine. “We are a long way from getting a new drug, but in the short term we may look at screening a variety of compounds to see if they have the potential to block HSP101.”

Related Links:

Washington University School of Medicine
Burnet Institute
Deakin University



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