Loss‐of‐function analyses defines vital and redundant functions of the <i><scp>P</scp>lasmodium</i> rhomboid protease family

Lin, Jing-wen; Meireles, Patrícia; Prudêncio, Miguel; Engelmann, Sabine; Annoura, Takeshi; Sajid, Mohammed; Chevalley-Maurel, Séverine; Ramesar, Jai; Nahar, Carolin; Avramut, M. Cristina; Koster, Abraham J.; Matuschewski, Kai; Waters, Andrew P.; Janse, Chris J.; Mair, Gunnar R.; Khan, Shahid M.

doi:10.1111/mmi.12187

Cited by 42 publications

(50 citation statements)

References 67 publications

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“…Lack of crystalloid formation also has been reported for null mutants of the crystalloid-resident LCCL protein PbSR (LAP1), although the block in sporogony is not absolute (8), and, more recently, also for parasites lacking LAP3 (9). Gene deletion mutants of additional LCCL/LAP protein family members (10,32,33), plasmepsin VI (34) and rhomboid 3 (35), which may be bona fide crystalloid residents, present similar phenotypes with respect to oocyst differentiation. In P. berghei, hemozoin-containing vacuoles accumulate around the crystalloid's edges (4,28).…”

Section: Discussionmentioning

confidence: 80%

Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite

Santos

Duarte

Kehrer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Transmission of the malaria parasite from the mammalian host to the mosquito vector requires the formation of adequately adapted parasite forms and stage-specific organelles. Here we show that formation of the crystalloid-a unique and short-lived organelle of the Plasmodium ookinete and oocyst stage required for sporogonyis dependent on the precisely timed expression of the S-acyltransferase DHHC10. DHHC10, translationally repressed in female Plasmodium berghei gametocytes, is activated translationally during ookinete formation, where the protein is essential for the formation of the crystalloid, the correct targeting of crystalloid-resident protein LAP2, and malaria parasite transmission.T he malaria parasite is capable of infecting both the vertebrate host and mosquito vector. After a mosquito blood meal, sexual precursor cells rapidly differentiate into mature gametes. In the mosquito midgut, the gametes mate to form a zygote that develops further into the motile ookinete. After crossing the midgut epithelium and establishing a sessile oocyst, the ookinete gives rise to thousands of sporozoites capable of infecting a subsequent mammalian host (1).Sharing key organelles like the nucleus, endoplasmic reticulum, Golgi, and mitochondria with other eukaryotes, this parasite has evolved specialized, stage-specific structures that are necessary for developmental progression during parasite transmission. These include, for example, osmiophilic bodies (secretory vesicles) that release protein factors capable of lysing the parasitophorous vacuole and erythrocyte membranes, thus producing free gametes (2) and a gliding motility motor anchored to the inner membrane complex (IMC), allowing the ookinete to migrate across the mosquito midgut epithelium and establish an oocyst (3). Sporozoite formation in the oocyst finally requires the presence of a stage-specific organelle, the crystalloid, a multivesicular structure assembled in the ookinete and putative reservoir of proteins and lipids used during sporogony. Although this enigmatic organelle was discovered more than 40 y ago, its formation and function remain largely unknown (4-9). Six LCCL proteins have been shown to reside within (9) and maintain the stability (8, 9) of these organelles essential for sporogony (10).The morphological changes taking place during zygote-toookinete development and the generation of thousands of sporozoites inside a single oocyst require extensive protein translation and membrane biogenesis to support the formation of organelles and plasma membrane (PM) surrounding each new parasite. Onethird of the proteins identified in the oocyst and oocyst-derived (midgut) sporozoites of the human parasite Plasmodium falciparum are putatively membrane-bound (11). The targeting of such proteins to organelles, and perhaps formation of certain organelles per se, requires appropriate sorting signals, along with transmembrane (TM) domains to keep these factors in place. Posttranslational modifications, such as lipidation, can increase the affinity of a modif...

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Section: Discussionmentioning

confidence: 80%

Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite

Santos

Duarte

Kehrer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…2B) [35][36][37][38][39]. In the rodent malaria model Plasmodium berghei, ROM4 seems to be essential for the asexual life cycle in erythrocytes [40], whereas ROM1 seems to be dispensible. However, rhomboid deletion mutants of a Plasmodium yoelii model showed that ROM1 is important for parasitophorous vacuole formation and survival in the host cell [41].…”

Section: +mentioning

confidence: 99%

Intramembrane proteases as drug targets

Verhelst

2017

The FEBS Journal

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Proteases are considered attractive drug targets. Various drugs targeting classical, soluble proteases have been approved for treatment of human disease. Intramembrane proteases (IMPs) are a more recently discovered group of proteolytic enzymes. They are embedded in lipid bilayers and their active sites are located in the plane of a membrane. All four mechanistic families of IMPs have been linked to disease, but currently, no drugs against IMPs have entered the market. In this review, I will outline the function of IMPs with a focus on the ones involved in human disease, which includes Alzheimer's disease, cancer, and infectious diseases by microorganisms. Inhibitors of IMPs are known for all mechanistic classes, but are not yet very potent or selective – aside from those targeting γ‐secretase. I will here describe the different features of IMP inhibitors and discuss a list of issues that need attention in the near future in order to improve the drug development for IMPs.

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“…Their roles in the malaria parasite are known to be essential (Lin et al, 2013), and are thus widely considered to be prime candidates for next-generation anti-parasitic drugs. The substrate specificity of rhomboid proteases is one hallmark that distinguishes them from γ -secretase.…”

Section: Introductionmentioning

confidence: 99%

A Subset of Membrane-Altering Agents and γ-Secretase Modulators Provoke Nonsubstrate Cleavage by Rhomboid Proteases

Urban

Moin

2014

Cell Reports

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SUMMARY Rhomboid proteases are integral membrane enzymes that regulate cell signaling, adhesion, and organelle homeostasis pathways, making substrate specificity a key feature of their function. Interestingly, we found that perturbing the membrane pharmacologically in living cells had little effect on substrate processing, but induced inappropriate cleavage of non-substrates by rhomboid proteases. A subclass of drugs known to modulate γ-secretase activity acted on the membrane directly and induced non-substrate cleavage by rhomboid proteases, but left true substrate cleavage sites unaltered. These observations highlight an active role for the membrane in guiding rhomboid selectivity, and caution that membrane-targeted drugs should be evaluated for cross-activity against membrane-resident enzymes that are otherwise unrelated to the intended drug target. Further, some γ-secretase-modulating activity or toxicity could partly result from global membrane effects.

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Loss‐of‐function analyses defines vital and redundant functions of the Plasmodium rhomboid protease family

Cited by 42 publications

References 67 publications

Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite

Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite

Intramembrane proteases as drug targets

A Subset of Membrane-Altering Agents and γ-Secretase Modulators Provoke Nonsubstrate Cleavage by Rhomboid Proteases

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