bims-raghud 2025-02-23 papers

Issue of 2025–02–23
two papers selected by
Irene Sambri, TIGEM

Proc Natl Acad Sci U S A. 2025 Feb 25. 122(8): e2415422122

STING-induced noncanonical autophagy regulates endolysosomal homeostasis.

Tuozhi Huang, Chenglong Sun, Fenghe Du, Zhijian J Chen.

The cGAS-STING pathway mediates innate immune responses to cytosolic DNA. In addition to its well-established role in inducing inflammatory cytokines, activation of the cGAS-STING pathway also induces noncanonical autophagy, a process involving the conjugation of the ATG8 family of ubiquitin-like proteins to membranes of the endolysosomal system. The mechanisms and functions of STING-induced autophagy remain poorly understood. In this study, we demonstrated that STING activation induced formation of pH-elevated Golgi-derived vesicles that led to ATG16L1 and V-ATPase-dependent noncanonical autophagy. We showed that STING-induced noncanonical autophagy resulted in activation of the MiT/TFE family of transcription factors (TFEB, TFE3, and MITF), which regulate lysosome biogenesis. We found that lipidation of the ATG8 proteins, particularly GABARAPs, inhibited phosphorylation of MiT/TFE transcription factors by mTORC1. The lipidated GABARAPs bound to the Folliculin-interacting proteins (FNIPs), thereby sequestering the FNIP-folliculin protein complexes from activating mTORC1, resulting in dephosphorylation and nuclear translocation of MiT/TFE transcription factors. Furthermore, we found that STING-induced autophagy activated Leucine-rich repeat kinase 2 (LRRK2), a protein implicated in Parkinson's disease, through GABARAPs lipidation. We further showed that STING-induced autophagy induced ALIX-mediated ESCRT machinery recruitment to mitigate endolysosomal perturbation. These results reveal the multifaceted functions of STING-induced noncanonical autophagy in regulating endolysosomal homeostasis.

Keywords: ESCRT; STING; TFEB; autophagy; cGAS

DOI: https://doi.org/10.1073/pnas.2415422122

Epilepsy Behav. 2025 Feb 19. pii: S1525-5050(25)00052-6. [Epub ahead of print]165 110313

Behavioral analyses in rodent models of tuberous sclerosis complex.

Victor Rodrigues Santos, Lilian G Jerow, Candi L LaSarge.

Tuberous sclerosis complex (TSC) is typically associated with epilepsy, but patients also present with a myriad of comorbid neuropsychiatric disorders. TSC is caused by mutations in the tuberous sclerosis complex genes 1 or 2 (TSC1, TSC2). This TSC1/2 complex serves as a negative regulator of the mammalian target of rapamycin (mTOR) signaling pathway, which plays a crucial role in regulating neuronal function, including cell proliferation, survival, growth, and protein synthesis. Mutations result in hyperactivation of the pathway. Animal models with mutations in Tsc1 or Tsc2 consistently exhibit epilepsy and behavioral phenotypes. Additionally, abnormal neuronal populations can impact the broader network, leading to deficits in learning and memory, anxiety-like behaviors, deficits in social behaviors, and perseverative and repetitive behaviors. This review aims to synthesize the existing animal literature linking TSC models to epileptogenesis and behavioral impairments, with insights on how modifications in TSC signaling influence both the structure and function of neurons and behavior. Understanding these relationships may provide valuable insights into potential therapeutic targets for managing epilepsy and neuropsychiatric disorders associated with TSC dysregulation.

Keywords: Epilepsy; Seizures; TAND; Tuberous Sclerosis Complex; mTOR

DOI: https://doi.org/10.1016/j.yebeh.2025.110313