18 July 2024
New discovery reveals that Nup358, a nucleoporin resident of Annulate Lamellae (AL), an underexplored organelle, regulates ER-mitochondria connectivity
Credit: EMBO Reports (2024)
https://www.embopress.org/doi/full/10.1038/s44319-024-00204-8
A new study published in EMBO reports by researchers from the National Centre for Cell Science (NCCS), Pune, India, has shed light on the functions of relatively unknown subdomains of the endoplasmic reticulum (ER), called Annulate Lamellae (AL), in the regulation of ER-Mitochondrial contact sites (ERMCSs) – a current hot-spot for research.
AL are known to harbour a subset of nucleoporins, proteins conventionally known to form the nuclear pore complexes (NPCs). The nucleoporins at the NPCs mediate nucleo-cytoplasmic transport (NCT) – the movement of macromolecules such as proteins and RNAs into and out of the nucleus. However, the functions of the nucleoporins at the AL remain underexplored. The scientists at NCCS find that Nup358, an AL-resident nucleoporin, regulates the physical contacts between the ER and mitochondria. ERMCSs are shown to be crucial for coordinating critical cell processes such as mitochondrial activity, calcium homeostasis, lipid synthesis and transfer, etc. Moreover, given that disrupted ERMCSs are associated with a spectrum of diseases, ERMCS research has gained impetus in the past decade.
The team led by Dr. Jomon Joseph, in collaboration with Dr. Amitabha Majumdar’s group at NCCS, shows that Nup358 interacts with an ERMCS tether, the VAPB-PTPIP51 complex, and prevents growth factor-dependent activation of mTORC2/Akt, which has been previously shown to stabilize ERMCSs. The scientists also found that Nup358, in addition, facilitates GSK3β’s function in disrupting the contacts.
As ERMCSs are dynamically regulated to meet the cellular demands for energy, lipid synthesis and metabolic remodelling, the control of ERMCS connectivity by Nup358 highlights a cross-talk between different ER domains to fine tune the cellular response.
“Annulate lamellae have been a neglected organelle for decades since their original discovery in 1950s. Our study implicates AL in the regulation of ER-mitochondria connectivity through one of the resident nucleoporins, Nup358. It will be interesting to investigate the role of other nucleoporins that are present in the AL”, comments Dr. Jomon Joseph. The role of AL-associated Nup358 in mTORC2 regulation appears to be conserved in Drosophila, suggesting the significance of AL- associated functions in normal physiology.
Interestingly, impairment in NCT and in the functioning of ERMCSs have been independently implicated in the pathology of neurodegenerative diseases such as ALS, Huntington’s, Alzheimer’s disease, etc.
“The finding from our study indicates a cross-talk between NCT and ERMCS functions, and may provide new avenues to explore the molecular basis of the disease pathogenesis” says Dr. Joseph. “Moreover, mutations in Nup358 are associated with Acute Necrotizing Encephalopathy-I, a disease in which lesions develop in the brain in response to viral infections. It would be exciting to see if dysregulations of these newly uncovered functions of Nup358 could lead to the pathophysiology of the disease”.
Misha Kalarikkal, PhD, a recent graduate from NCCS, was the lead author of the paper. Rimpi Saikia, Lizanne Oliveira, Yashashree Bhorkar, Akshay Lonare, Pallavi Varshney, Prathamesh Dhamale and Amitabha Majumdar, PhD, from NCCS, were co-authors of the study.
This work was supported by Department of Biotechnology, Government of India (BT/PR27451/BRB/10/1655/2018), Science and Engineering Research Board, Department of Science and Technology, Government of India (SPR/2021/000352) and Pratiksha Trust Extra-Mural Support for Transformational Aging Brain Research (EMSTAR) (EMSTAR/20230-03) and intramural funding from NCCS. This study is published in EMBO Reports (July 2024).
https://www.embopress.org/doi/full/10.1038/s44319-024-00204-8