bims-lypmec 2023-07-02 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2023‒07‒02
ten papers selected by
Satoru Kobayashi
New York Institute of Technology

An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes.
Novel phosphorylation of Rab29 that regulates its localization and lysosomal stress response in concert with LRRK2.
Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel.
Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.
Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage.
Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis.
TRIM16-mediated lysophagy suppresses high-gluocse-accumulated neuronal Aβ.
Follicular lymphoma-associated mutations in the V-ATPase chaperone Vma21 activate autophagy by dysfunctional V-ATPase assembly.
Lysosomal storage disorders: from biology to the clinic with reference to India.
How Membrane Contact Sites Shape the Phagophore.

EMBO Rep. 2023 Jun 29. e56841

An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes.

Dale P Corkery, Sergio Castro-Gonzalez, Anastasia Knyazeva, Laura K Herzog, Yao-Wen Wu.

  Lysosomal membrane damage represents a threat to cell viability. As such, cells have evolved sophisticated mechanisms to maintain lysosomal integrity. Small membrane lesions are detected and repaired by the endosomal sorting complex required for transport (ESCRT) machinery while more extensively damaged lysosomes are cleared by a galectin-dependent selective macroautophagic pathway (lysophagy). In this study, we identify a novel role for the autophagosome-lysosome tethering factor, TECPR1, in lysosomal membrane repair. Lysosomal damage promotes TECPR1 recruitment to damaged membranes via its N-terminal dysferlin domain. This recruitment occurs upstream of galectin and precedes the induction of lysophagy. At the damaged membrane, TECPR1 forms an alternative E3-like conjugation complex with the ATG12-ATG5 conjugate to regulate ATG16L1-independent unconventional LC3 lipidation. Abolishment of LC3 lipidation via ATG16L1/TECPR1 double knockout impairs lysosomal recovery following damage.

Keywords:  TECPR1; autophagy; lysophagy; lysosome; membrane repair

DOI:  https://doi.org/10.15252/embr.202356841
J Cell Sci. 2023 Jun 27. pii: jcs.261003. [Epub ahead of print]

Novel phosphorylation of Rab29 that regulates its localization and lysosomal stress response in concert with LRRK2.

Tadayuki Komori, Tomoki Kuwahara, Tetta Fujimoto, Maria Sakurai, Ikuko Koyama-Honda, Mitsunori Fukuda, Takeshi Iwatsubo.

  Rab proteins are small GTPases that regulate a myriad of intracellular membrane trafficking events. Rab29 is one of the Rab proteins phosphorylated by leucine-rich repeat kinase 2 (LRRK2), a Parkinson's disease-associated kinase. Recent studies suggest that Rab29 regulates LRRK2, whereas the mechanism by which Rab29 is regulated remained unclear. Here we report a novel phosphorylation in Rab29 that is not mediated by LRRK2 and occurs under lysosomal overload stress. Mass spectrometry analysis identified the phosphorylation site of Rab29 as Ser185, and cellular expression studies of phosphomimetic mutants of Rab29 at Ser185 unveiled the involvement of this phosphorylation in counteracting lysosomal enlargement. PKCα and PKCδ were deemed to be involved in this phosphorylation and control the lysosomal localization of Rab29 in concert with LRRK2. These results implicate PKCs in the lysosomal stress response pathway comprised of Rab29 and LRRK2, and further underscore the importance of this pathway in the mechanisms underlying lysosomal homeostasis.

Keywords:  LRRK2; Lysosome; PKC; Phosphorylation; Rab29

DOI:  https://doi.org/10.1242/jcs.261003
Mol Cell. 2023 Jun 27. pii: S1097-2765(23)00426-4. [Epub ahead of print]

Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel.

Jiyuan Zhang, Weizhong Zeng, Yan Han, Wan-Ru Lee, Jen Liou, Youxing Jiang.

  Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology.

Keywords:  LAMP-1 and LAMP-2; TMEM175; lysosomal LAMP proteins; lysosomal hydrolytic function; lysosomal pH homeostasis; lysosome acidification; risk factor for Parkinson’s disease

DOI:  https://doi.org/10.1016/j.molcel.2023.06.004
Science. 2023 Jun 30. 380(6652): 1372-1380

Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.

Tao Zhang, Daichao Xu, Elijah Trefts, Mingming Lv, Hiroyuki Inuzuka, Guobin Song, Min Liu, Jianlin Lu, Jianping Liu, Chen Chu, Min Wang, Huibing Wang, Huyan Meng, Hui Liu, Yuan Zhuang, Xingxing Xie, Fabin Dang, Dongxian Guan, Yuqin Men, Shuwen Jiang, Cong Jiang, Xiaoming Dai, Jing Liu, Zhen Wang, Peiqiang Yan, Jingchao Wang, Zhenbo Tu, Mrigya Babuta, Emily Erickson, Alissandra L Hillis, Christian C Dibble, John M Asara, Gyongy Szabo, Piotr Sicinski, Ji Miao, Yu-Ru Lee, Lifeng Pan, Reuben J Shaw, Junying Yuan, Wenyi Wei.

Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.

DOI: https://doi.org/10.1126/science.abn1725
Front Immunol. 2023 ;14 1128700

Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage.

Yingting Hou, Hongbin He, Ming Ma, Rongbin Zhou.

  NLRP3 is an important innate immune sensor that responses to various signals and forms the inflammasome complex, leading to IL-1β secretion and pyroptosis. Lysosomal damage has been implicated in NLRP3 inflammasome activation in response to crystals or particulates, but the mechanism remains unclear. We developed the small molecule library screening and found that apilimod, a lysosomal disruptor, is a selective and potent NLRP3 agonist. Apilimod promotes the NLRP3 inflammasome activation, IL-1β secretion, and pyroptosis. Mechanismically, while the activation of NLRP3 by apilimod is independent of potassium efflux and directly binding, apilimod triggers mitochondrial damage and lysosomal dysfunction. Furthermore, we found that apilimod induces TRPML1-dependent calcium flux in lysosomes, leading to mitochondrial damage and the NLRP3 inflammasome activation. Thus, our results revealed the pro-inflammasome activity of apilimod and the mechanism of calcium-dependent lysosome-mediated NLRP3 inflammasome activation.

Keywords:  NLRP3 inflammasome; activation; apilimod; lysosome; mitochondria

DOI:  https://doi.org/10.3389/fimmu.2023.1128700
Korean J Physiol Pharmacol. 2023 Jul 01. 27(4): 311-323

Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis.

Yoona Jung, Wonjoon Kim, Na Kyoung Shin, Young Min Bae, Jinhong Wie.

  Ion homeostasis, which is regulated by ion channels, is crucial for intracellular signaling. These channels are involved in diverse signaling pathways, including cell proliferation, migration, and intracellular calcium dynamics. Consequently, ion channel dysfunction can lead to various diseases. In addition, these channels are present in the plasma membrane and intracellular organelles. However, our understanding of the function of intracellular organellar ion channels is limited. Recent advancements in electrophysiological techniques have enabled us to record ion channels within intracellular organelles and thus learn more about their functions. Autophagy is a vital process of intracellular protein degradation that facilitates the breakdown of aged, unnecessary, and harmful proteins into their amino acid residues. Lysosomes, which were previously considered protein-degrading garbage boxes, are now recognized as crucial intracellular sensors that play significant roles in normal signaling and disease pathogenesis. Lysosomes participate in various processes, including digestion, recycling, exocytosis, calcium signaling, nutrient sensing, and wound repair, highlighting the importance of ion channels in these signaling pathways. This review focuses on different lysosomal ion channels, including those associated with diseases, and provides insights into their cellular functions. By summarizing the existing knowledge and literature, this review emphasizes the need for further research in this field. Ultimately, this study aims to provide novel perspectives on the regulation of lysosomal ion channels and the significance of ion-associated signaling in intracellular functions to develop innovative therapeutic targets for rare and lysosomal storage diseases.

Keywords:  Autophagy; Ion channels; Lysosomal storage diseases; Lysosomes

DOI:  https://doi.org/10.4196/kjpp.2023.27.4.311
Autophagy. 2023 Jun 25.

TRIM16-mediated lysophagy suppresses high-gluocse-accumulated neuronal Aβ.

Chang Woo Chae, Jee Hyeon Yoon, Jae Ryong Lim, Ji Yong Park, Ji Hyeon Cho, Young Hyun Jung, Gee Euhn Choi, Hyun Jik Lee, Ho Jae Han.

  Lysosomal dysfunction is a pathogenic link that may explain the causal relationship between diabetes and Alzheimer disease; however, there is no information about the regulation of hyperglycemia in neuronal lysophagy modulating lysosomal function. We examined the effect and related mechanisms of action of high glucose on lysophagy impairment and subsequent Aβ accumulation in human induced pluripotent stem cell (hiPSC)-derived neurons, mouse hippocampal neurons, and streptozotocin (STZ)-induced diabetic mice. High-glucose-induced neuronal lysosomal dysfunction through reactive oxygen species-mediated lysosomal membrane permeabilization and lysophagy impairment. Among lysophagy-related factors, the expression of TRIM16 (tripartite motif containing 16) was reduced in high-glucose-treated neuronal cells and the diabetic hippocampus through MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1)-mediated inhibition of TFEB (transcription factor EB) activity. TRIM16 overexpression recovered lysophagy through the recruitment of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), SQSTM1/p62, and ubiquitin to damaged lysosomes, which inhibited the high-glucose-induced accumulation of Aβ and p-MAPT/tau. In the diabetic mice model, TFEB enhancer recovered lysophagy in the hippocampus, resulting in the amelioration of cognitive impairment. In conclusion, TRIM16-mediated lysophagy is a promising candidate for the inhibition of diabetes-associated Alzheimer disease pathogenesis.

Keywords:  Amyloid β; TFEB; TRIM16; autophagy; diabetes; hippocampal neuron; lysophagy

DOI:  https://doi.org/10.1080/15548627.2023.2229659
Autophagy Rep. 2022 ;1(1): 226-233

Follicular lymphoma-associated mutations in the V-ATPase chaperone Vma21 activate autophagy by dysfunctional V-ATPase assembly.

Ying Yang, Zhihai Zhang, Daniel J Klionsky.

  A significant number of follicular lymphoma patients display recurrent mutations in subunits and regulators of the vacuolar-type H+-translocating ATPase (V-ATPase). Past studies focusing on the role of these mutations highlighted essential functions of macroautophagy/autophagy, amino-acid, and nutrient-sensing pathways in the pathogenesis of this disease. Here, we demonstrate novel results understanding the role of the follicular lymphoma-associated hotspot mutation VMA21p.93X, which corresponds to Vma21[Δ66-77] in S. cerevisiae cells. We find that V-ATPase assembly is affected by the Vma21[Δ66-77] mutation, shown by decreased vacuolar levels of V0 subunits as well as a Vph1 stability assay. In addition, we report that vacuolar levels of histidine, lysine and arginine are significantly reduced in Vma21[Δ66-77] mutant cells. These results deepen the current understanding on the mechanism of how autophagy is activated by these mutations in follicular lymphoma.

Keywords:  Proton gradient; Vph1; stress; vacuole; yeast

DOI:  https://doi.org/10.1080/27694127.2022.2077509
Lancet Reg Health Southeast Asia. 2023 Feb;9 100108

Lysosomal storage disorders: from biology to the clinic with reference to India.

Jayesh Sheth, Aadhira Nair, Babban Jee.

  Lysosomal storage disorders (LSDs) are a group of seventy different metabolic storage diseases due to accumulation of substrate mainly in the form of carbohydrate, lipids, proteins, and cellular debris. They occur due to variant in different genes that regulate lysosomal enzymes synthesis, transport, and secretion. In recent years, due to an increased availability of various therapies to treat these disorders, and increased diagnostic tools, there has been an escalated awareness of LSDs. Due to heterogeneous population and various social reasons, India is likely to have a high frequency of LSDs. Therefore, to understand the burden of various LSDs, its molecular spectrum, and understanding the phenotype-genotype correlation, Indian Council of Medical Research (ICMR) and Department of Health Research (DHR), Government of India had set up a task force in the year 2015. It has resulted in identifying common LSDs, and founder variant for some of the storage disorders and molecular spectrum of various LSDs across the country. This review describes in detail the spectrum of LSDs, its molecular epidemiology and prevention in context to Indian population.

Keywords:  Burden; Diagnosis; Lysosomal storage disorders; Lysosomes; Prevention

DOI:  https://doi.org/10.1016/j.lansea.2022.100108
Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231162495

How Membrane Contact Sites Shape the Phagophore.

Cristina Capitanio, Anna Bieber, Florian Wilfling.

  During macroautophagy, phagophores establish multiple membrane contact sites (MCSs) with other organelles that are pivotal for proper phagophore assembly and growth. In S. cerevisiae, phagophore contacts have been observed with the vacuole, the ER, and lipid droplets. In situ imaging studies have greatly advanced our understanding of the structure and function of these sites. Here, we discuss how in situ structural methods like cryo-CLEM can give unprecedented insights into MCSs, and how they help to elucidate the structural arrangements of MCSs within cells. We further summarize the current knowledge of the contact sites in autophagy, focusing on autophagosome biogenesis in the model organism S. cerevisiae.

Keywords:  ER; autophagy; lipid transfer; membrane contact sites; vacuole

DOI:  https://doi.org/10.1177/25152564231162495