Biology subjects

Warscheid, B.

Publications and source records attributed to Warscheid, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization

Proteostasis failure is a hallmark of stress and disease, yet how it compromises mitochondrial integrity remains unclear. Here, we identify mitochondrial protein import as a critical pathway linking proteostasis failure to mitochondrial injury. We show that Raptinal, previously characterized as a rapid inducer of apoptosis, impairs the folding of newly synthesized proteins rather than directly disrupting mitochondrial membranes. The resulting proteotoxic stress drives mitochondrial outer membrane permeabilization and intrinsic apoptosis independently of BCL-2 family pore-forming proteins. VBIT4, a compound commonly used to maintain mitochondrial integrity, inhibited this pathway, and chemical proteomics with a photoaffinity analogue implicated the TIM23 import machinery. Genetic or pharmacological inhibition of the TIM23-PAM axis suppressed mitochondrial permeabilization without affecting canonical BAX-BAK-dependent apoptosis. These findings establish that mitochondrial protein import couples translation-associated proteotoxic stress to mitochondrial injury and identify regulation of import flux as a determinant of mitochondrial integrity during proteostasis failure.

cell biology↗

bioRxiv2026

MYC/MIZ1 suppression of lysosomal protein degradation drives immune evasion in pancreatic ductal adenocarcinoma

The MYC oncoprotein promotes immune evasion of pancreatic ductal adenocarcinoma (PDAC), but the underlying molecular mechanisms are not fully understood. Here we show that MYC protects PDAC tumors from CD4+ T cell-dependent elimination. Single cell sequencing shows that MYC suppression in tumor cells increases amino acid availability and broadly activates amino acid-responsive gene expression programs in immune cell populations. This occurs because MYC-driven uptake depletes free amino acids from tumor interstitial fluid and plasma, while MYC compromises macropinocytosis and autophagy, both of which depend on lysosomal protein degradation. MYC engages the POZ/BTB transcription factor MIZ1 to suppress lysosomal genes regulated by the TFE3/TFEB/MITF network or by free MIZ1, thereby inhibiting lysosomal protein degradation. An orthogonal genetic model enabling transient, selective inhibition of amino acid uptake in tumor cells recapitulates the effects of MYC depletion on amino acid levels in the tumor microenvironment and induces complete, CD4+ T cell-dependent tumor eradication with long-term survival. We propose that MYC-mediated, cell-autonomous disruption of lysosome function coupled to non-cell-autonomous protection from immune clearance allows MYC-low cells to benefit from MYC-high neighbors, such that intratumoral heterogeneity in MYC expression confers a selective advantage to the entire tumor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/740267v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@140d2ccorg.highwire.dtl.DTLVardef@cf5f1borg.highwire.dtl.DTLVardef@6d132aorg.highwire.dtl.DTLVardef@10535e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Structural Basis of Condensin Recruitment for X Chromosome Repression

In Caenorhabditis elegans, the condensin IDC complex represses transcription from both X chromosomes in hermaphrodites to achieve dosage compensation. How condensin IDC is specifically recruited to the X chromosomes in coordination with sex determination and dosage compensation (SDC) proteins and how it modulates gene expression have, however, remained unresolved. Here, we identify SDC-3 as the key adaptor that directly binds the elbow coiled-coil domain of the condensin IDC-specific SMC subunit DPY-27. Using cryo-electron microscopy, we determine the structure of the SDC-3 adaptor domain bound to an auto-inhibited condensin IDC holoenzyme. Disrupting this interaction compromises dosage compensation and diminishes condensin IDC enrichment on the X chromosomes. Upon overcoming auto-inhibition, condensin IDC exhibits robust DNA loop-extrusion activity comparable to that of canonical condensin. We propose that SDC-3-anchored condensin IDC exploits loop-extrusion to reorganize X-chromosome chromatin and mediate chromosome-wide transcriptional repression.

biochemistry↗

bioRxiv2025

Evolutionary Remodelling of a Remnant GET-Pathway Factor into PEX38, a Novel and Essential Peroxin in Euglenozoa

PEX19 is a cytosolic receptor that directs membrane proteins post-translationally to peroxisomes, as well as to mitochondria, lipid droplets, and the endoplasmic reticulum. A comprehensive Trypanosoma PEX19 interactome analysis uncovered PEX38 as a novel and essential Euglenozoa-specific peroxin. PEX38 contains distinct domains that bind the co- chaperone Hip and the PEX3-binding motif of PEX19, suggesting a role in stabilizing membrane protein and preventing premature membrane docking. PEX38 illustrates functional repurposing in organelle biogenesis. It originated from a remnant of the GET/TRC pathway, typically responsible for the targeting of tail-anchored proteins to the endoplasmic reticulum. While most components of this machinery are absent in Euglenozoa, PEX38 has been retained and adapted to mediate peroxisomal membrane protein targeting. This evolutionary adaptation is unique to Euglenozoa. Because the PEX19-PEX38 interaction is essential for parasite viability and PEX38 has no human homologs, this complex is a promising therapeutic target against trypanosomatid parasites.

cell biology↗

bioRxiv2025

The yeast peroxisomal proteome at absolute quantitative scale

Peroxisomes are dynamic organelles vital for lipid metabolism and redox homeostasis. In Saccharomyces cerevisiae, the expression of peroxisomal proteins is tightly regulated in response to metabolic conditions. Here, we provide the first absolute quantification of the yeast peroxisomal proteome under peroxisome-inducing (oleate) and fermentative (glucose) conditions using a label-free mass spectrometry approach. We determined protein copy numbers for [~]4,500 proteins, including 99 peroxisomal and peroxisome-associated proteins. Our data reveal that the peroxisomal proteome is [~]3-fold higher abundant in oleate-grown cells, constituting 2.8% of the total proteome (corresponding to 2.01 x 106 protein copies) compared to 0.8% (6.67 x 105 protein copies) in glucose, reflecting the necessity for peroxisomal functions such as fatty acid beta-oxidation. Enzymes of the beta-oxidation and glyoxylate cycle showed up to >500-fold higher abundance in oleate. In contrast, core components of the peroxisomal protein import machinery (e.g., Pex5, Pex14) exhibited only moderate changes ([~]2- to 8-fold). In addition to metabolic enzymes and components of the peroxisomal protein import pathways, we provide copy number data for proteins involved in cellular stress response, peroxisome proliferation, division and organization, peroxisome-associated membrane contact sites, and metabolite transporter. Taken together, our dataset offers a quantitative framework of peroxisomal remodeling under different metabolic conditions and highlights the organelles adaptive flexibility, providing a valuable resource for future studies on peroxisome biology.

cell biology↗

bioRxiv2025

Structure of Pex8 in complex with peroxisomal receptor Pex5 reveals its essential role in peroxisomal cargo translocation

Peroxisomes are essential cellular organelles that enable the sequestered execution of a broad range of metabolic processes. Due to the lack of an internal protein synthesis machinery, they entirely depend on the import of target proteins to carry out their functions within peroxisomes. While the process of cargo/receptor recognition is well understood, knowledge about the molecular mechanisms of the subsequent translocation steps, including cargo release and receptor recycling, is lacking behind. Here, we provide structural and functional evidence on the role of Pex8 in these processes. First, we show that Pex8 in yeast is essential for peroxisomal cargo translocation, irrespective of the mechanism of receptor/cargo recognition. Next, we reveal that Pex8 binds through an irregular twelvefold HEAT repeat array to a short three-helical bundle within the otherwise unfolded N-terminal domain of the Pex5 receptor. Impairing this interaction abolishes peroxisomal protein translocation. It is complemented by a secondary autonomous Pex8 cargo-like interaction site with the C-terminal domain of Pex5, thus generating a bipartite interaction between the two proteins. Our data support a model in which Pex5/Pex8 complex formation allows assembly with the peroxisomal Pex2/Pex10/Pex12 E3-ubiquitin ligase complex to initiate recycling of the receptor. In summary, our findings provide in-depth insight into the transition from cargo release into peroxisomes to receptor recycling, which is essential to uncover the overall process of the peroxisomal cargo translocation.

biophysics↗

bioRxiv2025

Microtubule anchoring and coupling of CD20 to the RhoA/Rock1 pathway

CD20 is a B cell-specific four-helix transmembrane protein and a prominent target of therapeutic anti-CD20 antibodies. CD20 is localized within a membrane nanocluster harboring the IgD class B cell antigen receptor (IgD-BCR) where it functions as a gatekeeper for the resting state of naive B lymphocytes. How CD20 exerts its gatekeeper function is not yet known. Using Ramos and human peripheral blood B cells, we show here that the serine/threonine kinase PKC{delta}, constitutively phosphorylates serine residues at the cytosolic tails of CD20. The phosphorylated CD20 becomes a target for 14-3-3 adaptor proteins that link CD20 to the RhoA GDP/GTP exchange factor GEF-H1 and the microtubule (MT) network controlling the stability of the IgD-BCR nanocluster. The binding of anti-CD20 antibodies results in MT disassembly and the replacement of the GEF-H1/CD20 complex by a RhoA-GTP/ROCK1/CD20 complex which drives actomyosin contractility. Our study suggests that CD20 not only maintains the resting state, but also orchestrates the MT/actin switch in active B lymphocytes. This could have implications for treatment with anti-CD20 antibodies and may help to optimize therapeutic protocols. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/656301v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1cfe15aorg.highwire.dtl.DTLVardef@d3ee14org.highwire.dtl.DTLVardef@1b375eforg.highwire.dtl.DTLVardef@103c9dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Beyond a Linear Structure: The Tubular Organization of the Tripartite Attachment Complex and the Functional Role of TAC53

The Tripartite Attachment Complex (TAC) is essential for mitochondrial DNA (kDNA) segregation in Trypanosoma brucei, providing a physical link between the flagellar basal body and the mitochondrial genome. Although the TACs hierarchical assembly and linear organization have been extensively studied, much remains to be discovered regarding its complete architecture and composition - for instance, our identification of a new TAC component underscores these knowledge gaps. Here, we use a combination of proteomics, RNA interference (RNAi), and Ultrastructure Expansion Microscopy (U-ExM) to characterize the TAC at high resolution and identify a novel component, TAC53 (Tb927.2.6100). Depletion of TAC53 in both procyclic and bloodstream forms results in kDNA missegregation and loss, a characteristic feature of TAC dysfunction. TAC53 localizes to the kDNA in a cell cycle-dependent manner and represents the most kDNA-proximal TAC component identified to date. U-ExM reveals a previously unrecognized tubular architecture of the TAC, with two distinct TAC structures per kDNA disc, suggesting a mechanism for precise kDNA alignment and segregation. Moreover, immunoprecipitation and imaging analyses indicate that TAC53 interacts with known TAC-associated proteins HMG44, KAP68, and KAP3, forming a network at TAC-kDNA the interface. These findings redefine our understanding of TAC architecture and function and identify TAC53 as a key structural component anchoring the mitochondrial genome in T. brucei. Significance StatementThis research identifies a new component (TAC53) of the tripartite attachment complex (TAC), a cellular machinery that anchors the mitochondrial DNA to a cytoskeletal structure, the basal body in Trypanosoma brucei. Using proteomics and high-resolution microscopy, we demonstrate that TAC53 is at the interface of the TAC and the mitochondrial DNA and likely the final piece in this structure. We also describe the overall tubular architecture of the TAC from the basal body to the mitochondrial matrix, and how the presence of two TAC structures per mitochondrial genome can explain the parasites ability to maintain its mitochondrial DNA accurately. In summary, we present a new component and the architecture of the currently best understood mitochondrial DNA segregation mechanism in biology.

cell biology↗

bioRxiv2025

TbTim20 facilitates protein import at a low membrane potential in trypanosomes lacking the mitochondrial genome

Protein import across the mitochondrial inner membrane typically depends on two protein translocases of the inner membrane (TIM) complexes and the membrane potential. The protozoan parasite Trypanosoma brucei, however, has a single, divergent TIM complex. Unlike other trypanosomal TIM subunits, TbTim20 is neither essential for normal growth of insect nor bloodstream forms of T. brucei, leaving its role uncertain. Specific mutations in the {gamma}-subunit of the F1FO-ATPase, such as {gamma}L262P, permit bloodstream form trypanosomes to grow without mitochondrial DNA (kinetoplast or kDNA). Here we show that RNAi-mediated depletion of TbTim20 inhibits growth of this cell line, but only if it lacks the kDNA. Titration of mitochondrial uncouplers and direct membrane potential measurements reveal that TbTim20 becomes more critical as the membrane potential decreases across all tested cell lines. Proteomic analysis of the uninduced and induced {gamma}L262P TbTim20-RNAi cell line, which lacks kDNA and exhibits the lowest membrane potential, shows depletion of a subset of imported proteins. This subset includes ATPase subunits, suggesting a mechanism by which TbTim20-silenced cell lines become more sensitive to uncouplers. Thus, we propose that TbTim20 supports import of a subset of proteins whose import is hypersensitive to a low membrane potential.

biochemistry↗

bioRxiv2024

Targeting the paralog protein for degradation accounts for the opposite roles of NRBP1 and NRBP2 in regulating LINE1 retrotransposition

Gene duplication generates paralogs undergoing diverse fates during evolution and serves as a potent catalyst of biological complexity. Paralogs frequently share redundant functions and may also exhibit antagonistic activities by competing for common interaction partners. Here we show that the gene paralogs NRBP1 and NRBP2 oppositely regulate LINE1 retrotransposition, via influencing integrity of the LINE1 ribonucleoprotein complex. We demonstrate that the opposite roles of NRBP1 and NRBP2 are not results of a competitive mechanism, but rather due to targeting NRBP1 for proteasome-mediated decay by NRBP2, probably through heterodimer formation. Moreover, our phylogenetic analysis shows that the regulatory function of NRBP2 may be acquired later during evolution, suggesting that evolutionary pressure has favored this functional fine-tuning of NRBP1. In summary, our discovery not only identifies NRBP1/2 as novel LINE1 regulators and implicates their involvement in human pathogenesis, but also provides a novel insight into the regulatory details arising from gene duplication.

cell biology↗

bioRxiv2024

PEX39 facilitates the peroxisomal import of PTS2 proteins

Peroxisomes are metabolic organelles essential for human health. Defects in peroxisomal biogenesis proteins (peroxins/PEXs) cause devastating disease. PEX7 binds newly synthesized proteins containing a type 2 peroxisomal targeting signal (PTS2) to enable their import from the cytosol into peroxisomes, although many aspects of this import pathway remain enigmatic. Utilizing in vitro assays, yeast, and human cells, we show that PEX39, a previously uncharacterized protein, is a cytosolic peroxin that facilitates PTS2-protein import by binding PEX7 and stabilizing its interaction with PTS2 cargo. PEX39 and PEX13, a peroxisomal membrane translocon protein, both possess a KPWE motif necessary for PEX7 binding. Sequential binding of PEX7 to this motif in PEX39 and PEX13 provides a novel paradigm for how PTS2 cargo engage the translocation machinery. Collectively, our work uncovers an ancient and functionally important relationship among PEX39, PEX7, and PEX13, offering insights that will advance our understanding of peroxisomal biogenesis and disease.

cell biology↗

bioRxiv2024

Integrative Omics reveals changes in the cellular landscape of yeast without peroxisomes

Peroxisomes are organelles that are crucial for cellular metabolism. However, these organelles play also important roles in non-metabolic processes, such as signalling. To uncover the consequences of peroxisome deficiency, we compared two extremes, namely Saccharomyces cerevisiae wild-type and pex3 cells, which lack functional peroxisomes, employing transcriptomics and quantitative proteomics technology. Cells were grown on acetate, a carbon source that involves peroxisomal enzymes of the glyoxylate cycle and does not repress peroxisomal proteins. Transcripts of peroxisomal {beta}-oxidation genes and the corresponding proteins were enhanced in pex3 cells. Peroxisome-deficiency also caused reduced levels of membrane bound peroxins, while the soluble receptors Pex5 and Pex7 were enhanced at the protein level. In addition, we observed alterations in non-peroxisomal transcripts and proteins, especially mitochondrial proteins involved in respiration or import processes. Our results not only reveal the impact of the absence of peroxisomes in yeast, but also represent a rich resource of candidate genes/proteins that are relevant in peroxisome biology. SummaryOmics comparison of wild-type and peroxisome-deficient (pex3) yeast cells uncovered processes that are affected by loss of peroxisomes. {beta}-oxidation enzymes were upregulated, whereas most peroxins were decreased. Also, several non-peroxisomal transcripts/proteins were significantly altered. Our data represent a rich source of candidate genes connected to peroxisome biology.

cell biology↗

bioRxiv2024

Coordination of cytochrome bc1 complex assembly at MICOS

The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as determinant in the biogenesis of the cytochrome bc1 complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruitment of complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, directly contributes to the spatial and temporal coordination of respiratory chain biogenesis.

biochemistry↗

bioRxiv2024

Intermembrane space-localized twin Cx9C motif-containing TbTim15 is an essential subunit of the single mitochondrial inner membrane protein translocase of trypanosomes

All mitochondria import >95% of their proteins from the cytosol. This process is mediated by protein translocases in the mitochondrial membranes, whose subunits are generally highly conserved. Most eukaryotes have two inner membrane protein translocases (TIMs) that are specialized to import either presequence-containing or mitochondrial carrier pro-teins. In contrast, the parasitic protozoan Trypanosoma brucei has a single TIM complex consisting of one conserved and five unique subunits. Here, we show that the trypanoso-mal TIM complex contains an additional trypanosomatid-specific subunit, designated TbTim15. TbTim15 is associated with the TIM complex, lacks transmembrane domains and localizes to the intermembrane space. TbTim15 is essential for procyclic and bloodstream forms of trypanosomes. It contains two twin CX9C motifs and mediates import of both, presequence-containing and mitochondrial carrier proteins. While the precise function of TbTim15 in mitochondrial protein import is unknown, our results are consistent with the notion that it may function as an import receptor for the non-canonical trypanosomal TIM complex.

biochemistry↗

bioRxiv2024

Autoprot: Processing, Analysis and Visualization of Proteomics Data in Python

MotivationThe increasing numbers of complex quantitative mass spectrometry-based proteomics data sets demand a standardised and reliable analysis pipeline. For this purpose, Python-based analysis, particularly through Jupyter notebooks, serves as a simple yet powerful tool. Nevertheless, the availability of Python software for standardised and accessible MS data analysis is limited, and this software is often constrained to using analysis functions written in Python. This excludes existing and well-tested software, for example written in R. Despite this, Python offers several interactive data visualisation modules that greatly enhance exploratory research and facilitate result communication with collaboration partners. Consequently, there is a need for an integrated and Jupyter-compatible Python analysis pipeline that incorporates R algorithms and interactive visualization for proteomics data analysis. SummaryWe developed autoprot, a Python module for simplified analysis of quantitative mass spectrometry-based proteomics experiments processed with the MaxQuant software. It provides access to established functions written in both Python and R for statistical testing and data transformation. Moreover, it generates JavaScript-based interactive plots that can be integrated into interactive web applications. Thereby, autoprot offers standardised, fast and reliable proteomics data analysis while maintaining the high customisability required to tailor the analysis pipeline to specific experiments. Availability and ImplementationAutoprot is implemented in Python [≥] 3.9 and can be downloaded from https://github.com/ag-warscheid/autoprot. Online documentation is available at https://ag-warscheid.github.io/autoprot/.

bioinformatics↗

bioRxiv2024

Cardiac stress leads to regulation of Filamin C dimerisation via an ancient phosphorylation-modulated interaction with HSPB7

The biomechanical properties and responses of tissues underpin a variety of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. Seemingly a multi-functional protein that interacts with a variety of partners, how FLNC is regulated at the molecular level is not well understood. Here we have investigated its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We found that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we have solved by means of X-ray crystallography. Our quantitative analyses show that the hetero-dimer out-competes the FLNC homo-dimer interface, potentially acting to abrogate the ability of the protein to cross-link the actin cytoskeleton, and to enhance its diffusive mobility. We show that phosphorylation of FLNC at threonine 2677, located at the dimer interface and associated with cardiac stress, acts to favour the homo-dimer. Conversely, phosphorylation at tyrosine 2683, also at the dimer interface, has the opposite effect and shifts the equilibrium towards the hetero-dimer. Evolutionary analysis and ancestral sequence reconstruction reveals this interaction and its mechanisms of regulation to date around the time primitive hearts evolved in chordates. Our work rationalises on the molecular level how FLNC might switch between stabilising functions in the cell, and reveals how HSPB7 acts as a specific molecular chaperone that regulates FLNC.

molecular biology↗

bioRxiv2023

Evolutionary repurposing of trypanosomal Pam18 and Pam16 reveals a new regulatory circuit for mitochondrial genome replication

Protein import and genome replication are essential processes for mitochondrial biogenesis and propagation. The J-domain proteins Pam16 and Pam18 regulate the presequence translocase of the mitochondrial inner membrane. In the protozoan Trypanosoma brucei, their counterparts are TbPam16 and TbPam18, which are essential for the procyclic form of the parasite, though not involved in mitochondrial protein import. Here, we show that during evolution, the two proteins have been repurposed to regulate the replication of maxicircles within the intricate kDNA network, the most complex mitochondrial genome known. TbPam18 and TbPam16 have inactive J-domains suggesting a function independent of heat shock proteins. However, their single transmembrane domain is essential for function. Pulldown of TbPam16 identifies a putative client protein, termed MaRF11, the depletion of which causes the selective loss of maxicircles, akin to the effects observed for TbPam18 and TbPam16. Moreover depletion of the mitochondrial proteasome results in increased levels of MaRF11. Thus, we propose a model for a membrane-bound regulatory circuit that controls maxicircle replication in response to an unknown nuclear signal. This model posits that MaRF11 directly mediates maxicircle replication, that its level is controlled by proteasomal digestion, and that it is protected from degradation by binding to the TbPam18/TbPam16 dimer.

biochemistry↗

bioRxiv2023

High confidence glycosomal membrane protein inventory unveils trypanosomal Peroxin PEX15

Infections by trypanosomatid parasites cause Chagas disease, Human African Trypanosomiasis, and Leishmaniasis, affecting over 12 million people worldwide. Glycosomes, the unique peroxisome-related organelles of trypanosomes are essential for their survival, and hence their metabolic functions and biogenesis mediated by peroxins (PEX) are suitable as drug targets. Here we report on a comprehensive protein inventory of glycosomal membranes through advanced subcellular membrane protein profiling employing quantitative mass spectrometry. Our quantitative analysis resulted in the identification of 28 novel high confidence glycosomal membrane proteins. Our in-depth protein inventory of glycosomal membranes serves as an important resource for characterizing glycosome biology and drug development. We validated four so far unknown glycosomal membrane proteins, including two tail-anchored (TA) proteins, a homolog of human peroxisomal PXMP4, and a Macrodomain-containing protein. Using a structure-based approach, we identified one of the TA proteins as the long-sought Trypanosoma PEX15. Despite its low sequence similarity, Trypanosoma PEX15 exhibits structural and topological similarities with its yeast (Pex15) and human counterparts (PEX26). We show that PEX15 is an essential integral glycosomal membrane protein that interacts with PEX6. Accordingly, RNAi knockdown of PEX15 in bloodstream form trypanosomes demonstrates that it is essential for glycosome biogenesis and parasite survival. Considering the low degree of conservation with its human counterpart, PEX15 is a promising molecular target for drug development.

cell biology↗