Biology subjects

Saladi, S.

Publications and source records attributed to Saladi, S..

3 recordsLinked to original sources

bioRxiv2026

TIM22 Complex-NADH dehydrogenase crosstalk maintains mitochondrial health by modulating cell death

Programmed cell death is essential for organismal development. When dysregulated, it leads to neurodegenerative diseases and cancer. Although apoptotic pathways are well studied, the role of mitochondrial import translocases in regulating cell death remains unclear. Our study reveals a unique apoptotic pathway controlled by the TIM22 complex, an inner mitochondrial membrane translocase. This pathway involves a multiprotein complex formed by Tim22 and Nde1, a part of the respiratory electron transport chain. Under stress, the cytosol-exposed Nde1 isoform, a pro-apoptotic factor, is stabilised by the TIM22 complex, which includes the Tim18 subunit and Tim22s transmembrane segments. Notably, impairing the TIM22 complex and deleting Nde1 suppresses apoptosis and restores mitochondrial health. Beyond its role in import, our study uncovers a moonlighting function of the TIM22 complex in regulating mitochondria-dependent apoptotic cell death.

Cell Biology↗

bioRxiv2022

Enhancer Reprogramming in Melanoma Immune Checkpoint Therapy Resistance

Immune checkpoint blockade (ICB) therapy has improved long-term survival for patients with advanced melanoma. However, there is critical need to identify potential biomarkers of response and actionable strategies to improve response rates. Through generation and analysis of 148 chromatin modification maps for 36 melanoma samples from patients treated with anti-PD- 1, we identified significant enrichment of active enhancer states in non-responders at baseline. Analysis of an independent cohort of 20 samples identified a set of 437 enhancers that predicted response to anti-PD-1 therapy (Area Under the Curve of 0.8417). The activated non-responder enhancers marked a group of key regulators of several pathways in melanoma cells (including c- MET, TGF{beta}, EMT and AKT) that are known to mediate resistance to ICB therapy and several checkpoint receptors in T cells. Epigenetic editing experiments implicated involvement of c-MET enhancers in the modulation of immune response. Finally, inhibition of enhancers and repression of these pathways using bromodomain inhibitors along with anti-PD-1 therapy significantly decreased melanoma tumor burden and increased T-cell infiltration. Together, these findings identify a potential enhancer-based biomarker of resistance to anti-PD-1 and suggest enhancer blockade in combination with ICB as a potential strategy to improve responses.

cancer biology↗

bioRxiv2019

The client-binding domain of the cochaperone SGTA/Sgt2 has a helical-hand structure that binds a short hydrophobic helix

The targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) into the correct membrane is critical for cellular homeostasis. The fungal protein Sgt2, and its human homolog SGTA, binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2 binding to TA IMP clients. We establish that the Sgt2 C-terminal region is flexible but conserved and sufficient for client binding. A molecular model for this domain reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA IMP clients with hydrophobic faces and a minimal length of 11 residues. This work places Sgt2 into a broader family of TPR-containing co-chaperone proteins.

biochemistry↗