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Published in final edited form as: Biochem Biophys Res Commun. 2020 Oct 17;533(4):1352–1358. doi: 10.1016/j.bbrc.2020.10.018

Transient elevation of temperature promotes cross-linking of α-crystallin-client proteins through formation of advanced glycation endproducts: A potential role in presbyopia and cataracts

Sandip K Nandi 1, Johanna Rankenberg 1, Marcus A Glomb 2, Ram H Nagaraj 1,3,*
PMCID: PMC7744422  NIHMSID: NIHMS1638918  PMID: 33081971

Abstract

The chaperone activity of α-crystallin is important for maintaining the transparency of the human lens. αB-crystallin (αBC) is a long-lived protein in the lens that accumulates chemical modifications during aging. The formation of advanced glycation end products (AGEs) through glycation is one such modification. αBC is a small heat shock protein that exhibits chaperone activity. We have previously shown that αBC-client protein complexes can undergo AGE-mediated interprotein cross-linking. Here, we demonstrate that short-term (1 h) exposure to elevated temperatures and methylglyoxal (MGO) during the chaperoning of client proteins by αBC promotes AGE-mediated interprotein cross-linking. Liquid chromatography/mass spectrometry (LC-MS/MS) analyses revealed the rapid formation of AGEs by MGO. Interestingly, we found that despite protein cross-linking, the chaperone activity of αBC increased during the transient elevation of temperature in the presence of MGO. Together, these results imply that transient and subtle elevation of temperature in the lens of the eye can promote protein cross-linking through AGEs, and if this phenomenon recurs over a period of many years, it could lead to early onset of presbyopia and age-related cataracts.

Keywords: Chaperone, α-crystallin, client proteins, protein cross-linking, AGEs

1. Introduction

The chaperone activity of α-crystallin (which consists of αA- and αB-crystallin subunits) is important for maintaining the transparency of the lens of the eye during aging [1]. This activity enables α-crystallin to bind to partially denatured client proteins in an ATP-independent manner, maintain them in a soluble state and prevent their further denaturation [2]. Other large heat shock proteins are likely to release the bound proteins and aid in the refolding of client proteins into their original conformation [3]. In the lens, α-crystallin binds to other crystallins, such as β- and γ-crystallins, other cytosolic proteins and cytoskeletal proteins, and prevents their denaturation during aging [4,5]. The absence of αA- or αB-crystallin results in gross morphological abnormalities of the lens and cataracts [6].

Similar to other long-lived proteins, such as collagen, α-crystallin in the lens accumulates chemical modifications during aging. One such modification is glycation, a reaction between amino groups (mainly those in lysine and arginine residues) in proteins with carbonyl compounds. Methylglyoxal (MGO) and ascorbate oxidation products are the major carbonyl compounds in the lens. The glycation reaction produces irreversible, structurally diverse adducts in proteins, which are collectively known as advanced glycation end products or AGEs [7]. Several AGEs have been identified in human lenses. Among these AGEs, Nε-carboxymethyllysine (CML), Nε-carboxyethyllysine (CEL), pentosidine, methylglyoxal-derived hydroimidazolone-1 (MGH-1), vesperlysine and glucosepane are quantitatively more abundant in human lenses [8,9]. AGEs progressively accumulate in aging lenses and accumulate at a higher rate in cataractous lenses [8,10]. The formation of AGEs can contribute to protein cross-linking and aggregation during aging and cataract formation.

Both in humans and animals, elevated environmental temperatures have been linked to cataract development. An association between earlier development of senile cataracts and higher environmental temperatures has been observed [11,12]. The development of cataracts in people with long-term exposure to low levels of infrared radiation has been ascribed to the elevation of temperature in the lens [13]. Dovrat and colleagues suggested that exposure of the lens to higher temperature is a cause of the higher incidence of cataracts in bakery workers [14]. To substantiate this claim, these authors incubated bovine lenses at 39.5°C and showed a direct relationship between a reduction in lens optical quality and the duration of exposure. Similarly, workers in the glass and molten metal industries, who work in high ambient temperatures, have a higher risk for developing cataracts than age-matched control subjects who do not work in these industries [15]. In addition, steel and iron industry workers have been reported to have an increased risk for cataract development [16,17]. Cotlier’s group reported that exposure of rabbits to high temperatures (42–49°C) resulted in an elevation of the temperature in the lens and posterior chamber by 3–5°C [18]. Several other reports in the literature have shown that the ocular temperature increases with increased ambient temperature [19,20]. Soderberg’s group reported that elevation of temperature from 37 to 43°C increases light scattering in rat lenses [21]. Exposure of Brown Norway rats to 35 ± 2°C for 3 weeks increased the incidence of cataracts compared to exposure to 24 ± 2°C [22]. Furthermore, organ cultured rat lenses incubated at 40–50°C developed cortical cataracts [23]. Thermal cataracts have also been observed in rabbits [24]. Heat has also been studied as a causal factor in the onset of presbyopia [25]; incubation of pig lenses at high temperature (50°C) replicated the age-associated stiffening of lenses [26]. Together, these studies suggest that elevated temperatures promote the onset of presbyopia and cataract formation, but the molecular mechanisms are not well understood.

We have previously demonstrated that α-crystallin-client protein complexes are stable under the conditions found in the lens, and the proximity of the two proteins makes them vulnerable to AGE-mediated interprotein cross-linking [10]. Based on these observations and those from previous studies that suggested elevated temperature as a cause of presbyopia and cataracts, we hypothesized that transient elevation of temperature in the lens results in rapid formation of α-crystallin-client protein complexes, which in the presence of carbonyl compounds, undergo interprotein cross-linking through AGEs. We tested this hypothesis by conducting chaperone assays with αBC at elevated temperatures for 1 h in the presence of MGO. Our results showed that during the 1 h incubation of the chaperone assay, MGO enhanced the chaperone activity of αBC and simultaneously promoted cross-linking between αBC and client proteins through AGEs. Together, our results suggest that transient elevation of temperature in the lens could lead to enhanced protein cross-linking via AGEs and could explain the earlier onset of presbyopia and cataracts in individuals exposed to high temperatures.

2. Materials and Methods

2.1. Materials.

MGO (Cat# 67028), citrate synthase (CS) (Cat# C3260), and malate dehydrogenase (MDH) (Cat# M1567) were obtained from Sigma-Aldrich (St, Louis, MO). The antibody against αBC was purified in our laboratory from a hybridoma culture obtained from Developmental Studies Hybridoma Bank, University of Iowa, IA. The antibodies against CS (Cat# 14309), MDH (Cat# 8610), anti-rabbit IgG (Cat# 7074) and anti-mouse IgG (Cat# 7076) were obtained from Cell Signaling Technology (Danvers, MA). All the other chemicals were of analytical grade. The cloning, expression and purification of recombinant αBC were performed as previously described [27].

2.2. Analysis of αBC’s chaperone activity in the presence or absence of MGO.

The chaperone activity of αBC was measured in a 96-well microplate using a microplate reader (Spectramax ID3, Molecular Devices, Sunnyvale, CA). A 200-μl assay mixture containing 0.2 mg/ml MDH, 0.6 mg/ml αBC, and 0–60 μM MGO in 50 mM phosphate buffer, pH 7.4, was incubated at 50°C for 1 h. CS aggregation assays were performed at 43°C with a 200-μl assay mixture containing 0.25 mg/ml CS, 0.6 mg/ml αBC and 0–60 μM MGO in 40 mM HEPES buffer, pH 7.4. Light scattering at 360 nm was monitored over a period of 1 h in a spectrophotometer.

2.3. Effect of MGO modification on αBC’s chaperone activity.

αBC (0.6 mg/ml) was incubated with 0–60 μM MGO at 25 or 50°C for 1 h in 50 mM phosphate buffer, pH 7.4. The samples were then dialyzed for 16 h against 50 mM phosphate buffer or 40 mM HEPES, pH 7.4, at 4°C. The chaperone activity of αBC was measured as described above.

2.4. Analyses of chaperone and client protein complexes.

Protein mixtures from the incubations described above containing 15 μg protein were analyzed by SDS-PAGE on 4–20% gradient gels under reducing conditions. Western blotting was performed as previously described [10]. The primary antibody dilutions used were 1:10,000 for the αBC antibody and 1:5,000 for the MDH and CS antibodies. The dilution used for the secondary antibodies was 1:5,000.

2.5. Measurement of AGEs.

AGEs were measured by LC-MS/MS, as previously described [10].

2.6. Statistical analysis.

All the data are presented as the means ± SDs from three independent experiments. One-way ANOVA with Dunnett’s multiple comparison tests using GraphPad Prism 7 software (San Diego, CA) was used to analyze the statistical significance of the data. A p value ≤ 0.05 was considered statistically significant.

3. Results

3.1. Short-term exposure to elevated temperature increases the MGO-mediated cross-linking of proteins.

The SDS-PAGE results showed that the cross-linked protein content in the αBC-MDH samples incubated with 10, 30 and 60 μM MGO for 1 h at 50°C was 50, 48 and 53% higher, respectively, than that in the samples incubated at 25°C (Fig. 1). The αBC-CS samples incubated at 43°C for 1 h with 10, 30 and 60 μM MGO contained 27, 49 and 51% more cross-linked proteins, respectively, than those incubated at 25°C (Fig. 1). To determine whether elevated temperature in the absence of the αBC-client protein complex can promote MGO-mediated cross-linking, αBC and MDH were incubated at 50 and 44°C, respectively, for 1 h in the presence or absence of 10–60 μM MGO, cooled at room temperature for 1 h and then mixed (Fig. 1, indicated with red numbers). Similarly, αBC and CS were incubated for 1 h at 43 and 37°C, respectively, in the presence or absence of 10–60 μM MGO, cooled for 1 h at room temperature and then mixed (Fig. 1, indicated with red numbers). The client proteins were thermally stressed at a slightly lower temperature to prevent their aggregation. The protein mixtures in which αBC and MDH were separately incubated at elevated temperatures (αBC at 50°C and MDH at 44°C) in the presence of 10, 30 and 60 μM MGO contained 31, 35 and 44% fewer protein cross-links, respectively, than the mixtures in which the two proteins were incubated together at 50°C. Similarly, when αBC and CS were separately incubated at elevated temperatures (αBC at 43°C and CS at 37°C) for 1 h, there were 36, 52 and 31% fewer protein cross-links with 10, 30 and 60 μM MGO, respectively, compared to the samples in which αBC and CS were incubated together at 43°C along with MGO. These data suggested that a brief exposure of αBC-client complexes to higher temperature along with MGO leads to higher protein cross-linking.

Figure 1: Transient exposure to elevated temperature in the presence of MGO induces nondisulfide cross-linking between αBC and client proteins.

Figure 1:

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αBC was incubated with MDH at 25 or 50°C for 1 h or with CS at 25 or 43°C in the presence or absence of 10–60 μM MGO. Subsequently, the protein mixtures (15 μg) were analyzed by SDS-PAGE on 4–20% gels under reducing conditions. The lanes with the highest levels of protein cross-links are indicated with black arrows. The lanes labeled with red numbers contain αBC and client proteins incubated separately for 1 h (with or without MGO), cooled at room temperature for 1 h and mixed. Densitometric analysis of the regions indicated with brackets was performed to quantify the cross-linked proteins. The bars are representative of the mean ± SD of three independent experiments. NS, not significant; *p<0.05; **p<0.01; ***p<0.001.

3.2. Transient elevation of temperature promotes interprotein cross-linking.

The short-term elevation of temperature (50°C) in the presence of MGO led to interprotein cross-linking between αBC and MDH, as evident from the western blotting results (Fig. 2). The contents of cross-linked proteins increased with increasing concentrations of MGO. Similar results were obtained for αBC and CS incubated with MGO at 43°C. Such cross-linking was not observed in the samples where αBC and client proteins (MDH or CS) were separately incubated at elevated temperature along with MGO (Fig. 2, indicated with red numbers). Together, these findings confirm that a short-term elevation in temperature promotes the increased interprotein cross-linking in chaperone-client protein mixtures in the presence of MGO.

Figure 2: Cross-linking between αBC and client proteins after a brief exposure to elevated temperature and MGO.

Figure 2:

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αBC and client proteins (CS and MDH) were mixed and incubated at 25, 43 or 50°C for 1 h in the presence or absence of 10–60 μM MGO. The incubation mixtures were analyzed by SDS-PAGE on 4–20% gels under reducing conditions and subjected to western blotting (for αBC, CS or MDH). Lanes indicated with black arrows show proteins with the highest degree of cross-linking. The lanes labeled with red numbers contain αBC and client proteins incubated separately for 1 h (with or without MGO), cooled at room temperature for 1 h and mixed.

3.3. Transient elevation of temperature enhances AGE formation in αBC-client protein complexes.

Methylglyoxal lysine dimer (MOLD) and methylglyoxal-derived imidazoline crosslink (MODIC) are two cross-linking AGEs produced by the reaction of MGO with proteins. MOLD is a lysine-lysine cross-linking structure, and MODIC is a lysine-arginine cross-linking structure (Fig. 3). The MODIC and MOLD levels in the αBC-MDH samples that were exposed to a transient elevation in temperature (50°C, 1 h) in the presence of 30 μM MGO were 2623.3 ± 116.8 and 10.1 ± 0.3 pmoles/μmole leucine equivalent, respectively, compared with 47.3 ± 4.4 and 0.26 ± 0.1 pmoles/μmole leucine equivalent, respectively, in the αBC-MDH samples that were exposed to ambient temperature (25°C) (Fig. 3). Similarly, the MODIC and MOLD levels were 561.3 ± 34.2 and 3.7 ± 0.3 pmoles/μmole leucine equivalent, respectively, in the αBC-CS samples that were exposed to a transient elevation in temperature (43°C) compared with 42.6 ± 5.6 and 0.25 ± 0.1 pmoles/μmole leucine equivalent, respectively, in the αBC-CS samples that were exposed to 25°C (Fig. 3). Such a rapid increase in the levels of cross-linking AGEs was not observed in the samples in which αBC (50 or 43°C), MDH (44°C) and CS (37°C) were separately exposed to elevated temperature in the presence of MGO for an hour. The MGO-derived noncross-linking AGEs CEL, argpyrimidine, MGH-1 and N7-carboxyethyl arginine (CEA) were also quantified (Fig. S1), and similar to the cross-linking AGEs, their levels were significantly elevated in the αBC-client protein complexes that were transiently exposed to elevated temperature in the presence of MGO. These results suggest that transient elevation of temperature causes greater accumulation of AGEs during the chaperoning of client proteins by αBC.

Figure 3. Transient elevation of temperature in the presence of MGO causes accumulation of cross-linking AGEs in αBC-client protein mixtures.

Figure 3.

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Estimation of AGEs in the αBC-MDH (top panels) and αBC-CS (bottom panels) samples by liquid chromatography/mass spectrometry. Temperatures marked in red indicate the temperatures at which αBC and client proteins (MDH or CS) were incubated separately in the presence or absence of MGO for 1 h, cooled for another hour at room temperature and mixed. The data presented are the mean ± SD of triplicate samples. ****p < 0.0001

3.4. Higher MGO-mediated protein cross-linking is accompanied by enhanced αBC’s chaperone activity.

We investigated the ability of MGO to modulate the chaperone activity of αBC. Fig. 4A shows that the chaperone activity of αBC remained unaltered in the presence of 10–30 μM MGO when MDH was used as the client protein. However, in the presence of 60 μM MGO, the activity improved by 5%. When CS was used as a client protein, the chaperone activity of αBC increased by 13, 12 and 13% in the presence of 10, 30 and 60 μM MGO, respectively. These data suggest that MGO-mediated AGE synthesis enhances the chaperone activity of αBC.

Figure 4: MGO increases the chaperone activity of αBC at elevated temperatures.

Figure 4:

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(A) Chaperone activity of αBC (0.6 mg/ml) in the presence or absence of 10–60 μM MGO was measured by the thermal aggregation of MDH (0.2 mg/ml) at 50°C in 200 μl of 50 mM phosphate buffer, pH 7.4, or the thermal aggregation of CS (0.25 mg/ml) at 43°C in 200 μl of 40 mM HEPES, pH 7.4. (B) αBC (0.6 mg/ml) was incubated in 50 mM phosphate buffer, pH 7.4, with or without MGO (10–60 μM) for 1 h at 25 or 50°C and then dialyzed against 50 mM phosphate buffer, pH 7.4, or 40 mM HEPES, pH 7.4. The chaperone activity of αBC (0.4 mg/ml) was measured by the thermal aggregation of MDH (0.15 mg/ml) or CS (0.25 mg/ml) as described above. The bar graphs are representative of the mean ± SD of triplicate measurements. NS, not significant; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

We then tested whether the higher chaperone activity was due to a direct effect of MGO on αBC. αBC was incubated with MGO at 25 or 50°C with 0–60 μM MGO for 1 h. The protein samples were then dialyzed against 50 mM phosphate buffer or 40 mM HEPES buffer, pH 7.4, and the chaperone activity was examined. The chaperone activity (against MDH aggregation) of αBC was unaltered after incubation at 50°C for 1 h or after incubation with 10–60 μM MGO at 25°C for 1 h (Fig. 4B). However, when αBC was incubated with 30 and 60 μM MGO at 50°C, 2 and 4% increases in chaperone activity were observed, respectively, compared with αBC incubated at 25°C. Similarly, in the CS aggregation assay, higher chaperone activity of αBC was observed when it was incubated at 50°C in the presence of MGO (24, 26 and 28% protection with 10, 30 and 60 μM MGO, respectively) than when αBC was incubated alone at 50°C (18% protection) or when αBC was incubated with 10, 30 and 60 μM MGO at 25°C (13, 16, 11% protection, respectively). Altogether, our results suggest that MGO-mediated modification of αBC during short-term exposure to elevated temperature improves its chaperone activity, which is accompanied by an increased propensity of αBC to undergo cross-linking with client proteins.

4. Discussion

Several previous studies have suggested that exposure to temperatures higher than ambient temperatures is a risk factor for presbyopia and cataract formation [11,28]. However, the mechanisms are not clear. We previously showed that the complex formed between α-crystallin and client proteins has a higher propensity to undergo interprotein cross-linking through AGEs and suggested that such a mechanism could play a role in lens aging and cataract formation [10]. Additionally, we demonstrated using human and mouse lenses that the accumulation of cross-linking AGEs contributes to the stiffening of lenses [10]. Based on those studies, we tested the hypothesis that transient elevation in temperature enhances interprotein cross-linking between α-crystallin and its client proteins through AGE formation. The present study demonstrated that transient elevation of temperature (43–50°C) promotes MGO-mediated cross-linking of αBC-client proteins, which is accompanied by accumulation of cross-linking AGEs. Such MGO-mediated increases in protein cross-linking and accumulation of AGEs were observed only during the 1 h incubation of αBC and client proteins (during the chaperone activity assay) but not when the αBC and client proteins were separately subjected (in the absence of the complex) to similar conditions, thus reinforcing the idea that αBC-client proteins become cross-linked during transient elevation of temperature. LC-MS/MS assays revealed that a transient elevation of temperature also increases the accumulation of noncross-linking AGEs in αBC-client protein mixtures. This phenomenon could be attributed to the altered conformation of the proteins when transiently exposed to elevated temperatures, resulting in an increased propensity of the chaperone and client proteins to undergo MGO-mediated modifications.

We used MGO as an AGE precursor in this study. The MGO concentration in human lenses is ~1.78 μM, and in rat lenses, it is ~2.1 μM [29,30]. Obviously, in our experiments, MGO concentrations were higher than those present in lenses. However, our study was conducted for just 1 h, which allowed the reaction of MGO with proteins during the chaperone activity assay. The lens proteins have a negligible turnover rate and therefore accumulate chemical modifications, including those from MGO, over a lifetime. Thus, although the lowest concentration of MGO we used was approximately 5 times higher than that present in the lens, we posit that the life-long occurrence of MGO reactions with α-crystallin favors the notion that transient elevation in temperature could enhance MGO-mediated cross-linking of lens proteins. It should also be noted that human lens has other glycation initiators, such as, ascorbate oxidation products and glucose [8,31,32], that could additionally contribute to protein cross-linking during a transient elevation of temperature.

Furthermore, we set the temperature to 43°C for αBC to chaperone CS and 50°C for αBC to chaperone MDH. These temperature settings were required for CS and MDH to undergo partial unfolding so that αBC could bind to them. Although temperature of the eye lens can increase with the elevation of ambient temperature in experimental animals (see Introduction), it is not known whether similar temperature increases occur in lenses of the eyes of humans exposed to high ambient temperatures, although this phenomenon is likely. We propose that the temperature of 43°C we used in the experiments with αBC-CS is more realistic than the temperature of 50°C that we used in the αBC-MDH experiments. Therefore, the experiments with αBC-MDH should be considered more as a proof of concept experiments than as representative of realistic occurrences in the lens. Despite these limitations, our study demonstrated that the chaperone activity of αBC is enhanced upon modification by MGO in a temperature-dependent manner. Such an enhancement could recruit more client proteins to interact with αBC. If αBC-client complexes remain tethered for a long period of time, which likely occurs in the human lens, as we suggested in our previous study [10], a transient elevation in ambient temperature, either due to natural or work-related, would promote interprotein cross-linking through AGE formation. Such cross-linking could lead to the formation of high-molecular weight protein aggregates and accelerate lens aging, causing presbyopia and cataract formation.

Supplementary Material

1

Highlights.

  • Elevated temperature and MGO increase αBC’s chaperone activity

  • Elevated temperature and MGO promote AGE synthesis in proteins

  • Elevation of temperature promotes MGO-mediated protein cross-linking by AGEs

Acknowledgement

We thank Ms. Clarinda Hougen for helping with the purification of αB and Drs. Rooban Nahomi and Mi-Hyun Nam for critical reading of the manuscript.

Funding

The work was supported by National Institute of Health Grants EY028836 and EY023286 (RHN) and an RPB grant to the Department of Ophthalmology, University of Colorado.

Abbreviations:

αBC

αB-crystallin

CS

citrate synthase

MDH

malate dehydrogenase

AGEs

advanced glycation end products

LC-MS/MS

liquid chromatography/tandem mass spectrometry

MGO

methylglyoxal

CEA

N7-carboxyethyl arginine

MGH-1

methylglyoxal-derived hydroimidazolone-1

CML

Nε-carboxymethyllysine

CEL

Nε-carboxyethyllysine

MOLD

methylglyoxal lysine dimer

MODIC

methylglyoxal-derived imidazoline crosslink

Footnotes

Conflict of interest: The authors declare that they have no conflicts of interest with the content of this work.

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