Biology subjects

Soleimanpour, S. A.

Publications and source records attributed to Soleimanpour, S. A..

4 recordsLinked to original sources

bioRxiv2021

The human disease gene CLEC16A encodes an intrinsically disordered protein region required for mitochondrial quality control

CLEC16A regulates mitochondrial health through mitophagy and is associated with over 20 human diseases. While CLEC16A has ubiquitin ligase activity, the key structural and functional regions of CLEC16A, and their relevance for human disease, remain unknown. Here, we report that a disease-associated CLEC16A variant lacks a C-terminal intrinsically disordered protein region (IDPR) that is critical for mitochondrial quality control. Using carbon detect NMR, we find that the CLEC16A C terminus lacks secondary structure, validating the presence of an IDPR. Loss of the CLEC16A C-terminal IDPR in vivo impairs pancreatic {beta}-cell mitophagy, mitochondrial function, and glucose-stimulated insulin secretion, ultimately causing glucose intolerance. Deletion of the CLEC16A C-terminal IDPR increases its self-ubiquitination and destabilizes CLEC16A, thus impairing formation of a critical CLEC16A-dependent mitophagy complex. Importantly, CLEC16A stability is dependent on proline bias within the C-terminal IDPR, but not amino acid sequence order or charge. Together, we clarify how an IDPR in CLEC16A prevents diabetes, thus implicating the disruption of IDPRs as novel pathological contributors to diabetes and other CLEC16A-associated diseases.

molecular biology↗

bioRxiv2021

Mitofusins 1 and 2 collaborate to fuel pancreatic beta cell insulin release via regulation of both mitochondrial structure and DNA content

The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in {beta}-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient {beta}-cells. Thus, the primary physiologic role of Mfn1 and 2 in {beta}-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.

cell biology↗

bioRxiv2020

TOLLIP promotes durable alveolar macrophage-mediated immunity during Mycobacterium tuberculosis infection by resolving cellular stress from lipids.

Relative deficiency of TOLLIP expression in monocytes is associated with increased tuberculosis (TB) susceptibility in genetic studies, despite antagonizing host innate immune pathways that control Mycobacterium tuberculosis (Mtb) infection. In this study, we investigated the mechanisms by which TOLLIP influences Mtb immunity. Tollip-/- mice developed worsened disease, consistent with prior genetic observations, and developed large numbers of foam cells. Selective TOLLIP deletion in alveolar macrophages (AM) was sufficient to induce lipid accumulation and increased Mtb persistence 28 days after infection, despite increased antimicrobial responses. We analyzed sorted, Mtb-infected Tollip-/- AM from mixed bone marrow chimeric mice to measure global gene expression 28 days post-infection. We found transcriptional profiles consistent with increased EIF2 signaling. Selective lipid administration to Tollip-/- macrophages induced lipid accumulation, and Mtb infection of lipid laden, Tollip-/- macrophages induced cellular stress and impaired Mtb control. EIF2 activation induced increased Mtb replication within macrophages, irrespective of TOLLIP expression, and EIF2 kinases were enriched in human caseous granulomas. Our findings define a critical checkpoint for TOLLIP to prevent lipid-induced EIF2 activation and demonstrate an important mechanism for EIF2 signaling to permit Mtb replication within macrophages.

immunology↗

bioRxiv2020

Mitophagy protects beta cells from inflammatory damage in diabetes

Inflammatory damage contributes to {beta}-cell failure in type 1 and 2 diabetes (T1D and T2D). Mitochondria are damaged by inflammatory signaling in {beta}-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent {beta}-cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient {beta}-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased {beta}-cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human {beta}-cell apoptosis. Thus, mitophagy promotes {beta}-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent {beta}-cell failure in diabetes and may be beneficial in other inflammatory conditions.

cell biology↗