bims-mecosi 2022-06-05 papers

Issue of 2022–06–05
four papers selected by
Verena Kohler, Stockholm University

FEBS Lett. 2022 Jun 01.

Membrane contact sites and cytoskeleton-membrane interactions in autophagy.

Patrick J Duckney, Pengwei Wang, Patrick J Hussey.

In Eukaryotes, organelle interactions occur at specialised contact sites between organelle membranes. Contact sites are regulated by specialised tethering proteins, which bring organelle membranes into close proximity, and facilitate functional crosstalk between compartments. Whilst contact site proteins are well characterised in mammals and yeast, the regulators of plant contact site formation are only now beginning to emerge. Having unique subcellular structures, plants must also utilise unique mechanisms of organelle interaction to regulate plant-specific functions. The recently characterised NETWORKED proteins are the first dedicated family of plant-specific contact site proteins. Research into the NET proteins and their interacting partners continues to uncover plant-specific mechanisms of organelle interaction and the importance of these organelle contacts to plant life. Moreover, it is becoming increasingly apparent that organelle interactions are fundamental to autophagy in plants. Here, we will present recent developments in our understanding of the mechanisms of plant organelle interactions, their functions, and emerging roles in autophagy.

Keywords: Actin; Autophagy; Chloroplast; Contact Site; Cytoskeleton; Endoplasmic Reticulum; Membrane; Mitochondria; Plasma Membrane; Vacuole

DOI: https://doi.org/10.1002/1873-3468.14414

J Cell Biol. 2022 Jul 04. pii: e202106046. [Epub ahead of print]221(7):

ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling.

William Hancock-Cerutti, Zheng Wu, Peng Xu, Narayana Yadavalli, Marianna Leonzino, Arun Kumar Tharkeshwar, Shawn M Ferguson, Gerald S Shadel, Pietro De Camilli.

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson's disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis.

DOI: https://doi.org/10.1083/jcb.202106046

Trends Immunol. 2022 May 27. pii: S1471-4906(22)00097-7. [Epub ahead of print]

Putative role of STING-mitochondria associated membrane crosstalk in immunity.

Chenyu Xue, Na Dong, Anshan Shan.

Stimulator of interferon genes (STING) has emerged as a key regulator of innate immunity, recognizing intracellular exogenous and endogenous DNA. Recent findings reveal that STING has multiple cell-specific immune functions in various pathological settings, including pathogenic infections, cancer, and autoimmune diseases. Here, we hypothesize that this unique location of STING in the mitochondria-associated membrane (MAM) might lead to the specificity of the cellular functions of STING mediated by mitochondria-ER communication. This new insight suggests that STING on the MAM might act as a hub that translates multiple cues on MAM into distinct cellular responses. This innovative view of STING biology might impart insights for future putative treatments in cancer and immune diseases that have been attributed to STING dysfunction.

DOI: https://doi.org/10.1016/j.it.2022.04.011

J Extracell Vesicles. 2022 Jun;11(6): e12233

Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles.

Simone M Crivelli, Caterina Giovagnoni, Zhihui Zhu, Priyanka Tripathi, Ahmed Elsherbini, Zainuddin Quadri, Jian Pu, Liping Zhang, Branislav Ferko, Dusan Berkes, Stefka D Spassieva, Pilar Martinez-Martinez, Erhard Bieberich.

The formation of extracellular vesicles (EVs) is induced by the sphingolipid ceramide. How this pathway is regulated is not entirely understood. Here, we report that the ceramide transport protein (CERT) mediates a non-vesicular transport of ceramide between the endoplasmic reticulum (ER) and the multivesicular endosome at contact sites. The process depends on the interaction of CERT's PH domain with PI4P generated by PI4KIIα at endosomes. Furthermore, a complex is formed between the START domain of CERT, which carries ceramide, and the Tsg101 protein, which is part of the endosomal sorting complex required for transport (ESCRT-I). Inhibition of ceramide biosynthesis reduces CERT-Tsg101 complex formation. Overexpression of CERT increases EV secretion while its inhibition reduces EV formation and the concentration of ceramides and sphingomyelins in EVs. In conclusion, we discovered a function of CERT in regulating the sphingolipid composition and biogenesis of EVs, which links ceramide to the ESCRT-dependent pathway.

Keywords: AlphaFold2; CERT; ER-endosome contact sites; HPA-12; NC03; PI4KIIIβ; PI4KIIIβ-IN-10; PI4KIIα; PI4P; Tsg101; ceramide; extracellular vesicles; sphingomyelin

DOI: https://doi.org/10.1002/jev2.12233