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@article{pmid41875162,

title = {Dynamic translocation of Inside-Out proteins to the cell surface underlies cellular adaptation to cancer-induced stress},

author = {Tomasz Slezak and Kelly M O'Leary and Tanya Guevara Avella and Natalia Musial and Jinyang Li and Anna Andrzejczak and Elizabeth F Scott and Duc Anh Le and Anthony A Kossiakoff},

doi = {10.1073/pnas.2529493123},

issn = {1091-6490},

year  = {2026},

date = {2026-03-01},

urldate = {2026-03-01},

journal = {Proc Natl Acad Sci U S A},

volume = {123},

number = {13},

pages = {e2529493123},

abstract = {Inside-Out (I-O) protein display, the noncanonical surface localization of intracellular proteins, represents an underexplored feature of tumor cell biology. Here, we map the molecular landscape and trafficking mechanisms that control the presentation of I-O proteins on cancer cell membranes. Employing APEX2-mediated proximity biotinylation and a custom antibody generation and validation platform, we identified approximately 140 high-confidence I-O proteins, primarily ribosomal, proteasomal, chaperone, and translation factors, notably enriched in protein families associated with stress-response pathways. Validation of 500 antibodies encompassing 40 I-O targets across seven tumor cell lines confirmed selective and robust surface localization, while in vivo imaging in mouse xenografts demonstrated pronounced and tumor-specific antibody accumulation. I-O proteins were absent on peripheral blood mononuclear cells (PBMCs) and in normal tissues, indicating cancer cell selectivity. Functional analyses revealed that I-O protein tethering to the membrane is dependent on heparan sulfate interactions; enzymatic removal of these glycans led to the clearance of I-O proteins from the cell surface. Notably, the removed proteins returned to baseline levels within 6 h, indicating a dynamic balance related to Endoplasmic Reticulum (ER)-Golgi trafficking and cellular stress. Nearly half of these I-O proteins overlapped with known stress granule (SG) components; however, stress elements that promote SG formation do not similarly affect surface display of I-O proteins. Furthermore, I-O proteins are present on standard cancer cell lines under lower stress levels needed to induce SG formation, suggesting parallel yet mechanistically distinct aspects of the stress response. These findings position I-O display as a paradigm in protein trafficking, different from traditional secretion pathways and closely linked to stress response.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41818370,

title = {Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer},

author = {Corleone S Delaveris and Rita P Loudermilk and Apurva Pandey and Soumya G Remesh and Trenton M Peters-Clarke and Snehal D Ganjave and William J N Dougherty and Henry M Delavan and Chunyue Wang and Jesse Ling and Juan Antonio Camara Serrano and Fernando Salangsang and Chien-Kuang Cornelia Ding and Nancy Greenland and Carissa E Chu and Sima Porten and Veronica Steri and Jonathan Chou and Michael J Evans and Kevin K Leung and James A Wells},

doi = {10.1126/science.aec1778},

issn = {1095-9203},

year  = {2026},

date = {2026-03-01},

urldate = {2026-03-01},

journal = {Science},

volume = {391},

number = {6790},

pages = {eaec1778},

abstract = {Overexpression of the proto-oncogene Src is common to a wide variety of cancers. In this work, we found that Src is noncanonically translocated and inverted onto the cell surface in cancer, both in vitro and in vivo. We identified autophagolysosomal exocytosis (ALE) as a secretory mechanism prominent in cancer cell lines. Src represents the prototypical example of a family of membrane-anchored proteins that are transported by this process. Furthermore, this extracellular membrane-associated Src (eSrc) was found in primary tumors, and anti-Src antibody-based therapies mediated tumor cell killing in cell culture systems and in mouse xenograft models. Thus, intracellular -myristoylated proteins, prototypically Src, can be topologically inverted onto the cell surface in cancer and targeted with antibody therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41807832,

title = {Structures of ALG3/9/12 reveal the assembly logic of the N-glycan oligomannose core},

author = {J Andrew N Alexander and Shu-Yu Chen and Somnath Mukherjee and Mario de Capitani and Rossitza N Irobalieva and Lorenzo Rossi and Parth Agrawal and Julia Kowal and Matheus A Meirelles and Markus Aebi and Jean-Louis Reymond and Anthony A Kossiakoff and Sereina Riniker and Kaspar P Locher},

doi = {10.1038/s41589-026-02164-7},

issn = {1552-4469},

year  = {2026},

date = {2026-03-01},

urldate = {2026-03-01},

journal = {Nat Chem Biol},

abstract = {Asparagine-linked glycans are essential for the maturation and function of most eukaryotic secretory proteins. The biosynthesis and transfer of dolichylpyrophosphate-anchored GlcNAcManGlc glycan is a highly conserved process occurring in the endoplasmic reticulum (ER) membrane and involving over a dozen membrane proteins whose dysfunction is linked to congenital disorders of glycosylation (CDGs). Three membrane-integral mannosyltransferases, ALG3, ALG9 and ALG12, mediate four consecutive mannosylation reactions that convert GlcNAcMan to GlcNAcMan. Here, using chemoenzymatically synthesized lipid-linked glycan donor and acceptor analogs, we recapitulated this biosynthetic pathway in vitro. High-resolution cryo-electron microscopy structures of pseudo-Michaelis complexes of each step revealed how the branched glycan is accurately synthesized and unwanted side products are averted. Molecular dynamics simulations and mutagenesis studies uncovered a subtle but precise mechanism selecting the dolichylphosphomannose donor substrate over dolichylphosphoglucose, which is also present in the ER membrane. Our results also provide mechanistic explanations for enzyme dysfunction in CDGs and offer opportunities for N-glycan engineering.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}