Structural and mechanistic insights into secretagogin-mediated exocytosis

Qin, Jiao; Liu, Qi; Liu, Zhe; Pan, Yun Zu; Sifuentes-Dominguez, Luis; Stepien, Karolina P.; Wang, Yan; Tu, Yingfeng; Tan, Shuxin; Wang, Yuan; Sun, Qingxiang; Mo, Xianming; Rizo, Josep; Burstein, Ezra; Jia, Da

doi:10.1073/pnas.1919698117

Cited by 27 publications

(21 citation statements)

References 58 publications

(75 reference statements)

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“…Co-immunoprecipitation. Cells are harvested and lysed in lysis buffer (50 mM Tris, pH 7.4, 50 mM NaCl, 0.5% Nonidet P-40) containing protease inhibitors (Bimake), similar to previous studies 64,65 . Lysates are centrifuged at 14,000g for 20 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Model-based analysis uncovers mutations altering autophagy selectivity in human cancer

et al. 2021

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Autophagy can selectively target protein aggregates, pathogens, and dysfunctional organelles for the lysosomal degradation. Aberrant regulation of autophagy promotes tumorigenesis, while it is far less clear whether and how tumor-specific alterations result in autophagic aberrance. To form a link between aberrant autophagy selectivity and human cancer, we establish a computational pipeline and prioritize 222 potential LIR (LC3-interacting region) motif-associated mutations (LAMs) in 148 proteins. We validate LAMs in multiple proteins including ATG4B, STBD1, EHMT2 and BRAF that impair their interactions with LC3 and autophagy activities. Using a combination of transcriptomic, metabolomic and additional experimental assays, we show that STBD1, a poorly-characterized protein, inhibits tumor growth via modulating glycogen autophagy, while a patient-derived W203C mutation on LIR abolishes its cancer inhibitory function. This work suggests that altered autophagy selectivity is a frequently-used mechanism by cancer cells to survive during various stresses, and provides a framework to discover additional autophagy-related pathways that influence carcinogenesis.

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Section: Methodsmentioning

confidence: 99%

Model-based analysis uncovers mutations altering autophagy selectivity in human cancer

et al. 2021

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“…For the GST pull-down assay, HEK293T cells were transfected with various combinations of expression vectors, similar to previous studies ( Liu et al, 2020 ; Qin et al, 2020 ). The proteins were purified from cells using glutathione Sepharose beads in lysis buffer with protease and phosphatase inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of SNX27 by MAPK11/14 links cellular stress–signaling pathways with endocytic recycling

Mao

Liao

Qin

et al. 2021

Journal of Cell Biology

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Endocytosed proteins can be delivered to lysosomes for degradation or recycled to either the trans-Golgi network or the plasma membrane. It remains poorly understood how the recycling versus degradation of cargoes is determined. Here, we show that multiple extracellular stimuli, including starvation, LPS, IL-6, and EGF treatment, can strongly inhibit endocytic recycling of multiple cargoes through the activation of MAPK11/14. The stress-induced kinases in turn directly phosphorylate SNX27, a key regulator of endocytic recycling, at serine 51 (Ser51). Phosphorylation of SNX27 at Ser51 alters the conformation of its cargo-binding pocket and decreases the interaction between SNX27 and cargo proteins, thereby inhibiting endocytic recycling. Our study indicates that endocytic recycling is highly dynamic and can crosstalk with cellular stress–signaling pathways. Suppression of endocytic recycling and enhancement of receptor lysosomal degradation serve as new mechanisms for cells to cope with stress and save energy.

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“…Total RNA isolation and semi-quantitative RT-PCR RNA isolation and Semi-quantitative RT-PCR was carried out as previously described [30]. Fifty zebrafish embryos at indicated time point were collected for each sample.…”

Section: Zebrafish Knockdown and Mrna Injectionmentioning

confidence: 99%

GMPPB-congenital disorders of glycosylation associate with decreased enzymatic activity of GMPPB

et al. 2021

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The congenital disorders of glycosylation (CDG) are a family of metabolic diseases in which glycosylation of proteins or lipids is deficient. GDP-mannose pyrophosphorylase B (GMPPB) mutations lead to CDG, characterized by neurological and muscular defects. However, the genotype-phenotype correlation remains elusive, limiting our understanding of the underlying mechanism and development of therapeutic strategy. Here, we report a case of an individual presenting congenital muscular dystrophy with cerebellar involvement, who presents two heterozygous GMPPB mutations (V111G and G214S). The V111G mutation significantly decreases GMPPB’s enzymatic activity. By measuring enzymatic activities of 17 reported GMPPB mutants identified in patients diagnosed with GMPPB-CDG, we discover that all tested GMPPB variants exhibit significantly decreased enzymatic activity. Using a zebrafish model, we find that Gmppb is required for neuronal and muscle development, and further demonstrate that enzymatic activity of GMPPB mutants correlates with muscular and neuronal phenotypes in zebrafish. Taken together, our findings discover the importance of GMPPB enzymatic activity for the pathogenesis of GMPPB-CDG, and shed light for the development of additional indicators and therapeutic strategy.

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Structural and mechanistic insights into secretagogin-mediated exocytosis

Cited by 27 publications

References 58 publications

Model-based analysis uncovers mutations altering autophagy selectivity in human cancer

Model-based analysis uncovers mutations altering autophagy selectivity in human cancer

Phosphorylation of SNX27 by MAPK11/14 links cellular stress–signaling pathways with endocytic recycling

GMPPB-congenital disorders of glycosylation associate with decreased enzymatic activity of GMPPB

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