bims-apauto 2021-09-26 papers

Issue of 2021–09–26
five papers selected by
Su Hyun Lee, Seoul National University

Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00692-4. [Epub ahead of print]81(18): 3803-3819.e7

Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.

Keywords: AMP; AMPK; IMPA1; energy stress; glucose deprivation; inosiotl sensor; inositol; inositol/AMP ratio; mitochondrial fission; mitocondrial dynamics

DOI: https://doi.org/10.1016/j.molcel.2021.08.025

J Mol Cell Biol. 2021 Sep 25. pii: mjab059. [Epub ahead of print]

Membrane dynamics of ATG4B and LC3 in autophagosome formation.

Yuanyuan Zhou, Zhenkun Wang, Yijia Huang, Chujie Bai, Xianli Zhang, Mengdie Fang, Zhenyu Ju, Bo Liu.

The biogenesis of autophagosomes provides the basis for macroautophagy to capture and degrade intracellular cargoes. Binding of the autophagy-related protein ATG8/LC3 to autophagic membranes is essential to autophagosome formation, which involves the specific and dynamic processing of ATG8/LC3 by cysteine protease ATG4. However, to date, the mechanism whereby ATG4 is recruited to the membranes, the interaction of ATG4 and ATG8/LC3 on the membranes, and its role in the growth of phagophore are not completely understood. Here, we used fluorescence recovery after photobleaching to monitor the turnover of GFP-tagged ATG4B and LC3B in living animal cells. The data show that ATG4B localizes to early autophagic membranes in an LC3B-dependent manner. During autophagy, ATG4B and LC3B undergo rapid cytosol/isolation membrane exchange but not at the cytosol/completed autophagosome. In addition, ATG4B activity controls the efficiency of autophagosome formation by impacting the membrane binding/dissociation of LC3B. These data suggest that ATG4 and LC3 play interdependent roles in the formation of autophagosomes.

Keywords: ATG4; LC3; autophagosome biogenesis; autophagy; live-cell imaging; membrane binding kinetics

DOI: https://doi.org/10.1093/jmcb/mjab059

Mol Cell. 2021 Sep 18. pii: S1097-2765(21)00729-2. [Epub ahead of print]

PKCλ/ι inhibition activates an ULK2-mediated interferon response to repress tumorigenesis.

Juan F Linares, Xiao Zhang, Anxo Martinez-Ordoñez, Angeles Duran, Hiroto Kinoshita, Hiroaki Kasashima, Naoko Nakanishi, Yuki Nakanishi, Ryan Carelli, Luca Cappelli, Esperanza Arias, Masakazu Yashiro, Masaichi Ohira, Sanjay Patel, Giorgio Inghirami, Massimo Loda, Ana Maria Cuervo, Maria T Diaz-Meco, Jorge Moscat.

The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCλ/ι inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

Keywords: STING; ULK1/2; atypical PKC; autophagy; chaperone-mediated autophagy; colorectal cancer; immunosuppression; immunosurveillance; immunotherapy; interferon

DOI: https://doi.org/10.1016/j.molcel.2021.08.039

IUBMB Life. 2021 Sep 22.

Regulation of innate immune signaling pathways by autophagy in dengue virus infection.

Shu-Wen Wan, Ying-Ray Lee, Tzong-Shiann Ho, Chih-Peng Chang.

Autophagy is not only an intracellular recycling degradation system that maintains cellular homeostasis but is also a component of innate immunity that contributes to host defense against viral infection. The viral components as well as viral particles trapped in autophagosomes can be delivered to lysosomes for degradation. Abundant evidence indicates that dengue virus (DENV) has evolved the potent ability to hijack or subvert autophagy process for escaping host immunity and promoting viral replication. Moreover, autophagy is often required to deliver viral components to pattern recognition receptors signaling for interferon (IFN)-mediated viral elimination. Hence, this review summarizes DENV-induced autophagy, which exhibits dual effects on proviral activity of promoting replication and antiviral activity to eliminating viral particles.

Keywords: antiviral immunity; autophagy; dengue virus; innate immune response; viral replication

DOI: https://doi.org/10.1002/iub.2554

Cell Death Dis. 2021 Sep 22. 12(10): 858

Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFκB signaling.

Yinghui Ren, Limin Cao, Limin Wang, Sijia Zheng, Qicheng Zhang, Xueru Guo, Xueqin Li, Mengmeng Chen, Xiang Wu, Fiona Furlong, Zhaowei Meng, Ke Xu.

Tumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that autophagy was upregulated in lung cancer-associated CAFs compared to normal fibroblasts (NFs), and autophagy was responsible for the promoting effect of CAFs on non-small cell lung cancer (NSCLC) cell migration and invasion. Inhibition of CAFs autophagy attenuated their regulation on epithelial-mesenchymal transition (EMT) and metastasis-related genes of NSCLC cells. High mobility group box 1 (HMGB1) secreted by CAFs mediated CAFs' effect on lung cancer cell invasion, demonstrated by using recombinant HMGB1, HMGB1 neutralizing antibody, and HMGB1 inhibitor glycyrrhizin (GA). Importantly, the autophagy blockade of CAFs revealed that HMGB1 release was dependent on autophagy. We also found HMGB1 was responsible, at least in part, for autophagy activation of CAFs, suggesting CAFs remain active through an autocrine HMGB1 loop. Further study demonstrated that HMGB1 facilitated lung cancer cell invasion by activating the NFκB pathway. In a mouse xenograft model, the autophagy specific inhibitor chloroquine abolished the stimulating effect of CAFs on tumor growth. These results elucidated an oncogenic function for secretory autophagy in lung cancer-associated CAFs that promotes metastasis potential, and suggested HMGB1 as a novel therapeutic target.

DOI: https://doi.org/10.1038/s41419-021-04150-4