Biology subjects

Nair, S. V.

Publications and source records attributed to Nair, S. V..

3 recordsLinked to original sources

bioRxiv2025

Injectable Immune-Engineered Hydrogel Niche Remote From The Immune Suppressed Tumor Microenvironment For Cancer Immunotherapy

Immunocompromise is a hallmark of cancer, affecting both the peripheral immune system and local tumor microenvironment (TME). Current immunotherapies like checkpoint inhibitors, CAR-T cells, and neo-antigen vaccines show limited efficacy due to severe immunosuppression in most patients. Here, we report an immunologically engineered injectable nano-hydrogel (iHG) that can: (i) recruit the desired set of immune cells away from the suppressed TME and peripheral organs, (ii) activate them within a protective ambit of engineered immune-stimulatory hydrogel niche, and (iii) release them to target cancer even in distant locations. Biodegradable and injectable iHG compositions were tested and optimized for their ability to attract and activate dendritic cells, macrophages, monocytes, NK cells, B cells, and T cells via STING, TLR, CD86, and Th1-polarized cytokine pathway without requiring exogenously introduced neo-antigens as vaccines. In a mouse melanoma model, optimized iHGs elicited a robust antitumor immune response through innate and adaptive arms. Most importantly, iHGs as a single agent immunomodulator exhibited better tumor control than when combined with anti-PD1 immune checkpoint antibody. These findings highlight the potential of engineering immunologically functional and injectable hydrogel niches as a new type of immunotherapeutics to reprogram immune cells to overcome both local and systemic immunosuppression and combat cancer effectively.

immunology↗

bioRxiv2025

Lysosomal Glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway to Parkinsons disease

Mutations in LRRK2 and GBA1 are the most common genetic causes of familial Parkinsons disease. Previously, we showed that pathogenic LRRK2 mutations inhibit primary cilia formation in rare interneurons and astrocytes of the mouse and human dorsal striatum. This blocks Hedgehog signaling and reduces synthesis of neuroprotective GDNF and NRTN, which support neurons vulnerable in PD. Here we show that GBA1 mutations also impair Hedgehog signaling through a distinct mechanism. Loss of GBA1 activity decreases accessible cholesterol in primary cilia of cultured cells, thereby disrupting Hedgehog signaling. In the mouse striatum, Gba1 mutations result in reduced Hedgehog-induced Gdnf RNA expression in cholinergic interneurons, despite having no detectable impact on cilia formation. Also, both Lrrk2 and Gba1 mutations suppress Hedgehog-induced Bdnf expression in striatal astrocytes. These findings underscore the role of Hedgehog signaling in the nigrostriatal circuit and reveal a convergent mechanism by which distinct mutations may contribute to PD pathogenesis.

neuroscience↗

bioRxiv2019

Naturally Occurring Shorter and Tumor-associated Mutant RNF167 Variants Facilitates Lysosomal Exocytosis and Plasma Membrane Resealing

Lysosomal exocytosis and resealing of damaged plasma membrane play critical roles in physiological and pathological processes, including, restoration of cellular homeostasis and tumor invasion. However, to-date, only a few regulatory molecules of these biological processes have been identified. Moreover, no mutations in any of the known regulators of lysosomal exocytosis in primary tumors of patients have been characterized. Here we demonstrate that RNF167, a lysosomal associated ubiquitin ligase, negatively regulates lysosomal exocytosis by inducing perinuclear clustering of lysosomes. Importantly, we also characterized a set of novel natural mutations in RNF167, which are commonly found in diverse tumor types. We found that RNF167-K97N mutant, unlike the wild-type, localizes in the cytoplasm and does not promote perinuclear lysosomal clustering and that cells expressing RNF167-K97N exhibit dispersed lysosomes, increased exocytosis, and enhanced plasma membrane repair. Interestingly, these functional features of RNF167-K97N were shared with a naturally occurring short version of RNF167, i.e. isoform b. In brief, the results presented here reveal a novel role of RNF167 as well as its natural variants, RNF167-K97N and RNF167-b as an upstream regulator of lysosomal exocytosis and plasma membrane resealing which might play an important role in organelle dynamics or tumor progression or both.

cell biology↗