Biology subjects

Guo, S. S.

Publications and source records attributed to Guo, S. S..

4 recordsLinked to original sources

bioRxiv2026

Transmembrane-domain-driven heterodimer assembly licenses integrin head-domain folding in the endoplasmic reticulum

Integrins are a large family of /{beta} heterodimeric receptors whose activation is associated with the extension of the ectodomain and disruption of transient transmembrane domain (TMD) interactions. Whether the TMD interaction serves additional function(s) beyond regulating integrin activation remains unclear. Here, we report that three TMD-disruptive mutations within the integrin {beta}1-subunit activate its function while simultaneously reducing its surface expression. While a Gly744Asn ({beta}1-GN) and Gly744Leu ({beta}1-GL) TMD mutation yielded viable homozygous offspring, the more disruptive Leu748Arg ({beta}1-LR) TMD mutation caused embryonic lethality in mice and drastically reduced {beta}1-integrin surface levels. Cell biology and biochemistry studies revealed that TMD-TMD interactions drive efficient /{beta}-heterodimer assembly, thereby enabling the coupled folding of the ER-luminal {beta}I-domain. Disruption of these TMD interactions leads to endoplasmic reticulum (ER) retention and luminal domain-dependent ER-associated degradation of the monomeric, misfolded {beta}1-subunit. Moreover, mutations that disrupt the /{beta} TMD interaction of multiple integrin classes in humans similarly impair integrin cell surface expression and cause severe loss-of-function diseases. Together, our findings establish that /{beta} TMD association serves a previously unrecognized role in integrin biogenesis by promoting {beta}I-domain folding, preventing premature integrin activation in the ER, and ensuring the proper cell surface expression of activatable integrins.

cell biology↗

bioRxiv2025

A cytoskeletal scaffold promotes motile cilia assembly by regulating transition-zone integrity

Motile cilia are eukaryotic organelles with essential chemo- and mechano-sensing functions across evolution, from single cell organisms to humans. Motile cilia of the mammalian nervous, respiratory and reproductive systems are characterized by unique motility proteins to generate fluid flow essential for transporting metabolites and removing mucus. The molecular mechanism of motile cilia biogenesis remains unknown. Here, we use mouse genetics, single-molecule motility assays, proteomics, high-resolution imaging, and in situ cryo-tomography to identify mammalian KIF27, a motor protein of the Kinesin-4 family and homologue of the Hedgehog pathway regulator COS2/KIF7, as a key regulator of motile cilia assembly. We show that KIF27 promotes the integrity of the transition zone, a diffusion barrier situated at the cilium base. Loss of KIF27 causes specific and profound defects in axonemal structure and disrupts cilia beating, which collectively lead to organismal phenotypes that recapitulate primary ciliary dyskinesia. We show that the motile properties of KIF27 are dispensable for its function in motile cilia biogenesis. Instead, KIF27 acts as a microtubule scaffold to regulate the transition zone architecture and enable correct ciliary incorporation of motility-generating proteins. Given that KIF27 homologues exist in different evolutionarily lineages, we propose that the ancestral activities of KIF27/KIF7 kinesins were to form a microtubule-associated scaffold for protein-protein interactions pertinent to cilia formation and signaling. The transition-zone associated KIF27 activities may represent a general building principle for motile cilia assembly in diverse species and cell types.

developmental biology↗

bioRxiv2024

The USP12/46 deubiquitinases protect integrins from ESCRT-mediated lysosomal degradation

The functions of integrins are tightly regulated via multiple mechanisms including trafficking and degradation. Integrins are repeatedly internalized, routed into the endosomal system and either degraded by the lysosome or recycled back to the plasma membrane. The ubiquitin system dictates whether internalized proteins are degraded or recycled. Here, we used a genetic screen and proximity-dependent biotin identification to identify deubiquitinase(s) that control integrin surface levels. We found that a ternary deubiquitinating complex, comprised of USP12 (or the homologous USP46), WDR48 and WDR20, stabilizes {beta}1 integrin (Itgb1) by preventing ESCRT-mediated lysosomal degradation. Mechanistically, the USP12/46-WDR48-WDR20 complex removes ubiquitin from the cytoplasmic tail of internalized Itgb1 in early endosomes, which in turn prevents ESCRT-mediated sorting and Itgb1 degradation.

cell biology↗

bioRxiv2024

Rab7 deficiency induces lysosome formation from recycling endosomes leading to an increased degradation of cell surface proteins

Cell surface receptors such as integrins are repeatedly internalized from and recycled back to the plasma membrane before routed to lysosomes for degradation. In search for modulators of {beta}1 integrin surface stability, we identified the Rab7 small GTPase, believed to be required for lysosome biogenesis, as integrin stabilizer. We show that Rab7 deficiency produces late endosomes and lysosomes with acidic pH, lysosome-specific proteins and membrane architectures that are functional in protein degradation and organelle fusion. Furthermore, Rab7-deficient lysosomes form from Rab4- and transferrin receptor-positive recycling endosomes, resulting in the degradation of proteins designated for recycling. Finally, we also found that overexpression of Rab4 can direct lysosome formation from recycling endosomes in absence as well as presence of Rab7, however, the latter to a much lesser extent. Our findings reveal a lysosome biogenesis and lysosomal protein degradation pathway that becomes dominant in absence of Rab7 or when Rab4 is highly abundant.

cell biology↗