Open research questions in Cellular transport and secretion

What the literature leaves open

• The mechanism of syntaxin3-dependent TJ assembly in keratinocyte model cells is not fully understood. The role of Stx3 in TJ assembly is not well characterized. The key residues in Stx3 responsible for TJ assembly are not identified.

  Distinct mechanism of syntaxin3-dependent tight junction assembly in keratinocyte model cells · 2026 · DOI

• The paper identifies a gap in the development of effective furin inhibitors, which is essential for treating infectious and non-infectious diseases. The gap in understanding the specificity of furin and other proprotein convertases is highlighted. The need for potent and specific furin inhibitors is emphasized.

  Development and Prospects of Furin Inhibitors for Therapeutic Applications · 2024 · DOI

• Further studies are needed to clarify the association of Rab9 subfamily molecules with insufficient oligodendroglial cell differentiation and the hypomyelination phenotypes observed in HLD1. Additional research is needed to understand how the knockdown of Rab9, as well as that of Rab7B, decreases ER stress signaling in primary oligodendroglial cells and in mice.

  Knockdown of Rab9 Recovers Defective Morphological Differentiation Induced by Chemical ER Stress Inducer or PMD-Associated PLP1 Mutant Protein in FBD-102b Cells · 2024 · DOI

• Originally characterized as a recycling endosome t-SNARE, STX12 regulates tubular recycling and retrograde transport, yet its broader implications for lysosomal homeostasis remain poorly understood.

  Syntaxin 12 Sustains Endosomal‐Lysosomal Homeostasis and Survival in Glioblastoma Stem‐Like Cells · 2026 · DOI

• Endocytosis depends on plasma membrane (PM) lipid composition, yet how plants sustain endocytic machinery recruitment during stress remains unclear.

  Synaptotagmin-mediated plasma membrane homeostasis is required to recruit the endocytic machinery during cold stress · 2026 · DOI

• Endosomal maturation is closely associated with both lysosomal acidification and calcium signaling; however, the molecular mechanisms linking the Protrudin–PDZD8 complex to these processes remain unclear.

  TMEM55B Maintains Lysosomal Homeostasis and Promotes ER –Lysosome Calcium Signaling · 2026 · DOI

• Retrograde transport from endosomes to the trans-Golgi network (TGN) is essential for intracellular trafficking, yet its molecular mechanism remains poorly understood.

  Conserved Retrograde Trafficking Mechanisms Regulate Fungal Development and Pathogenicity Through Rab6‐GARP‐Retromer‐SNARE Coordination · 2026 · DOI

• While the phosphorylation of AHA2 induced by RALF1 has been well described, the ultimate fate of AHA2 following phosphorylation remains unclear.

  Spatiotemporal dynamics of AHA2 reveal that RALF1 induces its endocytosis and vacuolar degradation · 2025 · DOI

• Unlike the well-characterized molecular machinery of the conventional secretory pathway, the mechanisms underlying UcPS remain poorly understood.

  A Sensitive and Versatile Cell‐Based Assay Combines Luminescence and Trapping Approaches to Monitor Unconventional Protein Secretion · 2025 · DOI

• While prolonged depletion of GARP leads to severe trafficking and glycosylation defects, the primary defects linked to GARP dysfunction remain unclear.

  Acute GARP Depletion Disrupts Vesicle Transport, Leading to Severe Defects in Sorting, Secretion and O ‐Glycosylation · 2025 · DOI

• Fibroblast Growth Factor (FGF) signaling, a key regulator of skeletogenesis, has been linked to the autophagy-lysosomal pathway in chondrocytes, but its role in lysosome biogenesis remains poorly characterized.

  FGF Signaling Promotes Lysosome Biogenesis in Chondrocytes via the Mannose Phosphate Receptor Pathway · 2025 · DOI

• However, relatively little is known about the details of its secretory pathway ensuring the extremely high-level enzyme secretion and how they might be leveraged for engineering improved protein production.

  Distinct but Redundant Roles of ER Cargo Receptors p24 and Erv29 in Facilitating Proper Secretion of Cellulases in Trichoderma reesei · 2025 · DOI

• Vesicle transport is crucial for pathogenic fungi, but the mechanisms that control the secretion of effector proteins are not yet fully understood.

  Recycling of Trans‐Golgi SNAREs Promotes Apoplastic Effector Secretion for Effective Host Invasion in Magnaporthe oryzae · 2025 · DOI

• However, the specific functions across different cell types and tissues remain unclear.

  Knockdown of Rab9 Recovers Defective Morphological Differentiation Induced by Chemical ER Stress Inducer or PMD-Associated PLP1 Mutant Protein in FBD-102b Cells · 2024 · DOI

• Although the role of Rab27 in regulating exosome secretion has been reported, a systematic overview of how Rab27 contributes to tumorigenesis and cancer progression via exosome secretion, as well as its translational potential as a diagnostic biomarker and therapeutic target, is lacking.

  Rab27: Molecular switch of tumor exosome secretion (Review) · 2026 · DOI

• Many common inhibitors of CME have weak or no effects on plant CME. The mechanism of action of Ikarugamycin remains unknown. The study of plant CME is limited by the lack of specific inhibitors and the complexity of plant cellular constraints.

  Clathrin‐Mediated Endocytosis in Plants: Historical to Modern Advances · 2026 · DOI

• While the J-domain protein RME-8/DNAJC13 is known to maintain these boundaries by actively removing degradative machinery from the recycling microdomain, other factors that contribute to this spatial organization remain poorly defined.

  SCM-1/SCAMP Maintains Microdomain Boundaries and Cargo Sorting within the Endosomal System · 2026 · DOI

• How broadly expressed presynaptic proteins acquire the cell-type specificity needed to couple to CaV2 channels in defined neurons, and whether this specialization contributes to behavior, remains poorly understood.

  Nociceptor-enriched CAPS1 isoform couples to CaV2.2 channels and underlies inflammatory pain hypersensitivity · 2026 · DOI

• Two glycosites in the poorly characterized N-terminal intrinsically disordered region (IDR) of Sec24D, T9 and S13, display strikingly different dynamics: S13 is constitutively glycosylated, whereas T9 is rapidly modified following a synchronized burst of collagen transport and returns to baseline within minutes.

  Sugar on the Coat: Site‐Specific O‐ GlcNAc and Myoferlin Adapt COPII for Collagen Export · 2026 · DOI

• By identifying current knowledge gaps and providing future research directions, this review aims to stimulate further investigation into the multifaceted nature of lysosomal exocytosis and its implications for human health and disease.

  Unraveling Lysosomal Exocytosis: From Molecular Mechanisms to Physiological Functions · 2025 · DOI

• To demonstrate enhanced interaction of TIO kinase with Kin-12A/B upon binding of RAB-A2a in vitro. To identify the molecular substrates of TIO kinase activity. To explain how TIO-dependent phosphorylation of its substrates promotes phragmoplast formation and expansion.

  A Rab/Kinesin-12/kinase module couples vesicle delivery and phragmoplast dynamics during plant cell cytokinesis · 2026 · DOI

• Further investigation of the role of Rap1b in cAMP signaling. Exploration of the therapeutic potential of targeting Rap1b and AC9 in diseases related to cAMP signaling.

  Rap1 Activates Endosomal AC9 to Drive the Second cAMP Wave · 2026 · DOI

• Further study of the role of PI3K complex II in endosomal clathrin removal and lysosomal maturation. Investigation of the effects of PI3K complex II depletion on other cellular processes. Development of therapies for diseases related to endosomal dysfunction.

  The Uvrag-containing PI3K complex promotes Hsc70-4 dependent endosomal clathrin removal and lysosomal maturation in Drosophila nephrocytes · 2026 · DOI

• Further investigation of the mechanisms of PIKfyve regulation - Exploration of the potential therapeutic applications of enhancing PIKfyve activity - Examination of the role of PIKfyve in other cell types…

  PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity · 2026 · DOI

• The mechanisms by which photoreceptors eliminate misfolded or mistargeted proteins are not well understood - The specific role of disrupted PIP metabolism in retinal degenerative diseases remains poorly…

  PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity · 2026 · DOI

Most-cited papers in Cellular transport and secretion

• Studies and Perspectives of Protein Kinase C · Science · 1986 · 3,909 citations
• Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes · Science · 2008 · 3,248 citations
• Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase · Nature · 1999 · 2,879 citations
• SNAP receptors implicated in vesicle targeting and fusion · Nature · 1993 · 2,591 citations
• A Gene Network Regulating Lysosomal Biogenesis and Function · Science · 2009 · 2,367 citations
• Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification · Nature · 2010 · 2,269 citations
• Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics · Nature Nanotechnology · 2021 · 1,480 citations
• β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway · Cell · 2020 · 651 citations
• Tight junction proteins occludin and ZO‐1 as regulators of epithelial proliferation and survival · Annals of the New York Academy of Sciences · 2022 · 550 citations
• RAB31 marks and controls an ESCRT-independent exosome pathway · Cell Research · 2020 · 474 citations

Most recent work

• SNARE proteins: Core engines of membrane fusion in cancer · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · 2026
• Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis · Cell Research · 2026
• The ATG8 E3-like ligases sense lysosomal damage and initiate ESCRT-mediated membrane repair · The EMBO Journal · 2026
• Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer · Science · 2026
• PDS5 proteins control genome architecture by limiting the lifetime of cohesin-NIPBL complexes · Molecular Cell · 2026
• Endocytome profiling uncovers cell-surface protein dynamics underlying neuronal connectivity · Neuron · 2026
• In situ cryo-ET defines the ultrastructure of ER exit sites in human cells · Nature Cell Biology · 2026
• Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration · Autophagy · 2026
• Dual-engram architecture within a single striatal cell type distinctly controls alcohol relapse and extinction · Neuron · 2026
• Hybrid endosomal coats contain different classes of sorting nexins · The EMBO Journal · 2026

Related topics in Biochemistry, Genetics and Molecular Biology