Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis

Jiang, Mei; Esteve-Rudd, Julián; Lopes, Vanda S.; Diemer, Tanja; Lillo, Concepción; Rump, Agrani; Williams, David S.

doi:10.1083/jcb.201410112

Cited by 77 publications

(102 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This hypothesis was tested using various independent experimental approaches. Kinesin-1 light chain 1 (KLC1), the light chain subunit of microtubule motor kinesin 1, regulates motility of phagosomes and facilitates interactions between phagosomes and endosomes or lysosomes in the RPE (42). siRNA knockdown of KLC1 suppressed the rate of POS degradation in cultured RPE cells without affecting uptake (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Egbejimi

Dharmat

et al. 2018

Sci. Signal.

View full text Add to dashboard Cite

The retinal pigment epithelium (RPE) transports nutrients and metabolites between the microvascular bed that maintains the outer retina and photoreceptor neurons. The RPE removes photoreceptor outer segments (POS) by receptor-mediated phagocytosis, a process that peaks in the morning. Uptake and degradation of POS initiates signaling cascades in the RPE. Upstream stimuli from various metabolic activities converge on mechanistic target of rapamycin complex 1 (mTORC1), and aberrant mTORC1 signaling is implicated in aging and age-related degeneration of the RPE. In the current study, we measured mTORC1-mediated responses to RPE phagocytosis in vivo and in vitro. During the morning burst of POS shedding, there was transient activation of mTORC1-mediated signaling in the RPE. POS activated mTORC1 through lysosome-independent mechanisms and engulfed POS served as a docking platform for mTORC1 assembly. The identification of POS as endogenous stimuli of mTORC1 in the RPE provides a mechanistic link underlying the photoreceptor-RPE interaction in the outer retina.

show abstract

Section: Resultsmentioning

confidence: 99%

“…siRNA knockdown of KLC1 suppressed the rate of POS degradation in cultured RPE cells without affecting uptake (Fig. S5) (42). In contrast, POS-stimulated mTORC1 activity was comparable between control and KLC1-depleted cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Egbejimi

Dharmat

et al. 2018

Sci. Signal.

View full text Add to dashboard Cite

show abstract

“…Jiang et al found that POS phagosomes associate with myosin-VIIa and then kinesin-1 light chain 1 (KLC1), as they moved from the apical region of the RPE, and lack of KLC1 impairs phagosome degradation and RPE pathogenesis that was comparable to aspects of AMD, with an excessive accumulation of RPE and sub-RPE deposits, as well as oxidative and inflammatory stress responses. This research group demonstrated that defective microtubule motor transport in the RPE, such as transport of POS phagosomes in relation to degradation, leads to phenotypes associated with AMD (Jiang et al, 2015). …”

Section: Biomarkers In Heritability and Geneticsmentioning

confidence: 99%

Risk factors and biomarkers of age-related macular degeneration

Lambert

Elshelmani

Singh

et al. 2016

Progress in Retinal and Eye Research

291

240

View full text Add to dashboard Cite

A biomarker can be a substance or structure measured in body parts, fluids or products that can affect or predict disease incidence. As age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, much research and effort has been invested in the identification of different biomarkers to predict disease incidence, identify at risk individuals, elucidate causative pathophysiological etiologies, guide screening, monitoring and treatment parameters, and predict disease outcomes. To date, a host of genetic, environmental, proteomic, and cellular targets have been identified as both risk factors and potential biomarkers for AMD. Despite this, their use has been confined to research settings and has not yet crossed into the clinical arena. A greater understanding of these factors and their use as potential biomarkers for AMD can guide future research and clinical practice. This article will discuss known risk factors and novel, potential biomarkers of AMD in addition to their application in both academic and clinical settings.

show abstract

“…The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7)(8)(9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes mitochondrial stress, and induces secretion of VEGF and proinflammatory cytokines (11,12).…”

mentioning

confidence: 99%

Protective responses to sublytic complement in the retinal pigment epithelium

Tan

Toops

Lakkaraju

2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4 −/− Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4 −/− mice, indicating that they could be effective therapeutic approaches for macular degenerations.he complement system is an important regulator of immunity and inflammation. Complement activation by the classical, alternative, or lectin pathways results in the assembly of C5b-9 membrane attack complexes (MACs), which form membrane pores and cause target cell lysis. Within the eye, a low level of constant complement activity is necessary for immune surveillance, and several membrane-bound and soluble regulators prevent excessive complement activation (1). An imbalance between complement activation and inhibition in the retina is implicated in the pathogenesis of age-related macular degeneration (AMD), which causes central vision loss in more than 30 million people globally (reviewed in refs. 2-4).Evidence suggests that the retinal pigment epithelium (RPE), which helps maintain ocular immune privilege, is the first line of defense against unregulated complement activation in the retina (5). The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7-9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes...

show abstract

Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis

Cited by 77 publications

References 90 publications

Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium

Risk factors and biomarkers of age-related macular degeneration

Protective responses to sublytic complement in the retinal pigment epithelium

Contact Info

Product

Resources

About