ABSTRACT The heat shock response is a universal phenomenon in which an environmental stressor causes an animal to produce large quantities of heat shock proteins or HSPs. These proteins are thought to protect the cells from the damaging effects of stress, allowing the organism to recover from the shock and survive. In this study, the heat shock response was studied using the western blotting technique in the benthic sea cucumber, Psolus squamatus. An initial screening of the proteins from an unshocked specimen revealed a total of five proteins that cross-react with the anti-heat shock protein 60 antibody. P. squamatus generally lives in temperatures between 4°C and 7°C and in an ocean water salinity of 33.2 parts per thousand. Heat shocking the animals along a temperature gradient revealed that heat shock protein 60 production can be induced at 13°C, but protein synthesis appears to shut down and protein degradation may occur at super-ambient temperatures such as 20°C. Death occurs at 22°C. Salinity shock was at 10 g/L above and below the natural salinity of 33.2 g/L (parts per thousand). Results of the salinity shock appear a little more ambiguous and further study needs to be done before any conclusions are drawn. INTRODUCTION Heat shock proteins are present in all organisms and serve basic indispensable cellular functions (see 4, 6, 8 for review). They interact with other proteins in important ways such as aiding in intracellular trafficking of proteins and stabilizing proteins such as immunoglobulins. Heat shock proteins are among the most highly conserved between different species and therefore are very easy to detect. Their high degree of sequence homology allows for probing with antibodies made in different organism. The proteins occur in molecular weight families, of which there are four main types; the large molecular weight HSPs, the HSP 70 family, the HSP 60 family, and the small HSPs (15-30 KD). Proteins within each family share common amino acid sequences and cross react with the same antibody. They can, however, vary in size, but they generally fall into a narrow size range around which they are named. Heat shock proteins are present in the body at lower levels in the absence of stress. The stress response is characterized by a large scale induction of these proteins. The proteins are thought to protect the cells from the damaging effects of stress, allowing the stressed organism to recover and survive. Various stressors include heat shock, salinity shock, anoxia, pH variations, and contamination from different chemicals or xenobiotics in the environment. The stress response is universal. For this study, the stress response was studied in Psolus squamatus., a benthic sea cucumber that is found abundantly in the Monterey Canyon. It is an interesting organism to study because it is found at a very large depth distribution, ranging from 200 m to 3500 meters deep. The temperature varies with the depth, with colder temperatures occurring at deeper depths. P. squamatus is found to survive extreme environmental stresses with a great amount of success. Its natural habitat is in temperatures ranging between 4°C to 7°C. When exposed to a temperature gradient that ranged up to 25°C, the organisms were seen to survive in temperatures up to 22°C. Early studies of the heat-induced puffs in the fruit fly, Drosophila busckii, demonstrated that heat shock protein induction tended to interfere with oxidative phosphorylation or electron transport to protect cells from respiratory stress (6). A recent study in P. squamatus demonstrated that respiration increases with temperature between 2°C and 15°C (2). A heat shock response may be induced in P. squamatus' to aid the organism in surviving the temperature increase and the possible respiratory stress. The main goals of this project were to identify the heat shock proteins present constitutively in the animal and to study the effects of heat shock and salinity shock on heat shock protein induction. MATERIALS AND METHODS COLLECTION AND MAINTENANCE OF SPECIMENS: Psolus squamatus used in this study were collected with the MBARI ROV from various depths in the Monterey Bay Canyon. They were kept in the Deep Sea Lab of Hopkins Marine Station at an ambient sea water temperature of 5°C until needed. INDUCTION OF STRESS RESPONSE: • Heat Shock: Viable specimens were isolated in individual test tubes or jars and acclimated in Deep Sea Lab sea water (5°C) for 12-18 hours. Heat shock was induced by placing the jars containing the acclimated specimens into water baths previously set to heat shock temperatures. The individuals were shocked for a total of 2 hours. The control specimens were kept at 5°C for the duration of the heat shock. Individuals were shocked over a gradient of temperatures between 5.0 and 25.1°C. Individuals survived to an upper limit temperature of 22.0°C. • Salinity Shock: Specimens were isolated in individual jars and acclimated in a solution of Instant Ocean Synthetic Sea Salt, provided by Aquarium Systems of Mentor, ÖH, at a concentration of 33.2 parts per thousand (33.2 g Instant Ocean/1 L de ionized H2O) at 5°C for 12-18 hours. Individuals were shocked by decanting the 33.2 g/L solution and adding hypotonic (23.2 g/L) or hypertonic (43.2 g/L) solutions of Instant Ocean to the acclimated organism at 5°C for 3 hours. There were two salinity controls. The Instant Ocean control organism was acclimated at 5°C in a 33.2 g/L solution of Instant Ocean which was replaced with a new 33.2 g/L solution for the duration of the salinity shock. The other control was acclimated in normal Deep Sea Lab sea water at 5°C which was replaced with fresh Deep Sea Lab sea water at 5°C for the shock. The second control was to see whether the Instant Ocean Synthetic Sea Salt itself elicits a heat shock response. HOMOGENIZATION: Äfter shocking the organisms, the tentacle tissues were dissected and placed in 200 ul of homogenization buffer, consisting of PBS, EDTA, PMSF, pepstatin, leupeptin, chymostatin, and NP-40, and ground using a Teflon homogenizer. The sample was transferred to a 1.5 ml Eppendorf tube and centrifuged at 18,000 x g on a refrigerated microcentrifuge MTX-150 for 15 min. The supernatant was transferred to a new Eppendorf tube. Protein content was determined by adding 10 ul of the supernatant to 1 ml of de ionized H20 and 1 ml of Coomassie stain reagent and reading the sample at 595 nm on a Beckman DU-7 Spectrophotometer. A standard curve was used to determine the protein content from the spectrophotometer reading. An equal volume of 2X solubilizing buffer (7) containing DL¬ Dithiothreitol was added to the supernatant and boiled for 3 minutes to solubilize the protein. Samples were frozen at -20°C. SDS-PAGE: SDS-PAGE (10 % polyacrylamide) was carried out by Laemmli's method (5) to separate proteins according to size in reducing conditions. WESTERN BLOTTING: Western blots were prepared by Burnette's standard techniques (1). Two different transfer protocols were used, Hybond-ECL and Immobilon-P Transfer PVDF. The primary antibodies used included rabbit anti-60kD Heat Shock Protein (SPA-804), mouse anti-72kD HSP (SPA-801), mouse anti-72/73KD HSP (SPA-802), and mouse anti-90KD HSP (SPA-803), which were stored at -70°C and were provided by StressGen Biotechnologies Corporation in Victoria BC, Canada (product numbers in parentheses) and mouse anti-HSP 70 monoclonal antibody 3A3 that was stored at -20°C and was provided by Sean Murphy of Northwestern University. Dilutions were as follows: 1:1000 for anti-HSP 60, 1:10,000 for anti-HSP 70 3A3, 1:500 for anti D 70 HSr 72, 1:500 for anti-HSP 72/73, 1:300 for anti-HSP 90. Secondary antibodies included anti-mouse IgG peroxidase conjugate (Product No. A-4416) and anti¬ rabbit IgG peroxidase conjugate (Prod. No. A-4914) provided by Sigma Immuno Chemicals in St. Louis, MO and stored at -20°C. Both secondary antibodies were used at a 1:10,000 dilution. All antibodies were diluted in a total volume of 2.5 ml. Visualization of antibody binding was done using the Amersham Life Science ECL Western Blotting detection reagents RPM2109 and Kodak X-ÖMAT Scientific Imaging Film. Film was developed in a Konica X-ray film processor QX-60A. QUANTITATIVE ANALYSIS: Protein bands on western blots were analyzed using Jandel Scientific JAVA Version 3 Video Analysis Software. Eight intensity readings were taken of background and four intensity readings were taken of each band of interest. Background readings were averaged and subtracted from band intensity averages to produce relative intensities of the heat shock protein bands. It is assumed that there is a direct correlation between the intensity of the protein band and the amount of protein that was present in the specimen at the time of homogenization. RESULTS INITIAL SCREENING FOR HEAT SHOCK PROTEINS: Before the heat shock and salinity shock experiments were performed, two untreated specimens were homogenized in order to determine which heat shock proteins are present in the non-stressed organism. Table 1 (4/8 - 4/20) lists the results of this initial screening. There are at least two, and possibly three heat shock proteins that are recognized by the anti-HSP 60 antibody. The molecular weights of the two more prevalent HSP 60s are about 58 kD and 48 kD based upon the pre-stained molecular weight marker. The third HSP 60 protein, which appears fainter than the other two, appears at a molecular weight of about 55 kD. Figure 1 shows a western blot of untreated P. squamatus protein probed with anti-HSP 60. The lane on the left contains twice as much protein as the lane on the right. The 58 kD and the 48 kD proteins are visible in both lanes. Small quantities of the 55 kD protein can be seen in the lane on the right. Screening for HSP 70 proteins was done with three different primary antibodies, each of which has a small difference in binding affinity. Results show that there were no HSP 70 proteins present in the untreated organism. Screening with anti-HSP 90 showed that HSP 90 proteins were absent as well (see Table 1). P. SQUAMATUS PRODUCES AT LEAST FIVE HSP 60 PROTEINS: There appears to be five proteins that vary widely in molecular weight and cross-react with the anti-HSP 60 antibody. These five proteins can be seen in Figure 2. The lane on the left shows the three proteins that cross-react with the anti-HSP 60 antibody seen in Figure 1. The second lane contains the proteins of a control P. squamatus in a heat shock experiment that is producing an HSP 60 protein with a molecular weight of about 116 kD in addition to the three HSP 60 proteins seen in the left lane. The lane on the far right shows the proteins of a control P. squamatus in a salinity shock experiment that is producing a 40 kD protein that cross-reacts with the anti-HSP 60 antibody. Three of the proteins that are recognized by anti-HSP 60 (116, 55, 40 KD) appear sporadically throughout the experiments under different shock conditions and sometimes not at all. However, the 58 kD and the 48 kD proteins appear in every protein sample at different concentrations and intensities. The rest of this study focuses on these two proteins and the relative intensities of these HSP 60 bands as they appear on the western blots. EFFECT OF HEAT SHOCK ON THE 58 KD AND 48 KD PROTEINS RECOGNIZED BY ANTI-HSP 60: Figure 3 demonstrates the induction of protein synthesis at 12°C and the shutdown of protein synthesis and possible protein degradation at 19°C by western blot analysis of the HSP 60 proteins present in P. squamatus under different temperature shock conditions. The first lane contains the proteins of the control organism which was kept at 5°C during the heat shock. The second lane did not run properly. It contained the proteins of the organism shocked at 8°C. The third and fourth lanes contain the proteins of organisms shocked at 12°C and 19°C respectively. Equal amounts of protein were loaded into each of the lanes. Analysis of the darkness of each of the bands illustrates trends in the relative amount of protein in each shock condition compared to the control. Heat shock protein induction occurs at milder heat shock conditions and protein degradation occurs in the more drastic shocks. Figure 4 contains the quantitative analysis of the intensities of the 58 kD and the 48 kD protein bands on the western blot in Figure 3 based on data from the JAVA image processor. Specific values of the relative intensities are given in Table 1 (Expt. 5/25/93) under the "HSP 60 (58 kD)" and the "HSP 60 (48 kD)" columns. The numbers reported are the relative intensity (intensity of band minus the intensity of the background) values per ug of protein loaded per lane. In the higher molecular weight protein (58 kD), there is a dramatic increase in the amount of protein at 12°C and a decrease at 19°C. Levels of the lower molecular weight protein (48 kD) stay relatively constant in the organism between 5°C and 12°C but decrease at 19°C. It appears that heat shock protein production is induced during heat shock to aid the organism in dealing with the stress. However, there is a threshold temperature beyond which protein synthesis is inhibited and the organism is unable to manufacture any new proteins. Figures 5, 6, and 7 show the JAVA image processing analysis of the other three heat shock experiments that were run. Again, specific values can be found in Table 1. Figure 5 shows an increase in the amount of both the 58 kD and the 48 kD proteins after a heat shock of 2 hours at 13°C. Figure 6 shows a decrease in the amount of both the 58 kD and the 48 kD proteins after a heat shock of 2 hours at a super-ambient temperature of 19.6°C. Figure 7 shows a small increase in the amount of the 58 kD protein and a more significant decrease in the amount of the 48 kD protein present after a shock at a super-ambient temperature of 20.4C for two hours. The results of these three experiments serve to support the trend seen in Figures 3 and 4. The only inconsistency is in the increase of the 58 kD protein after a super-shock, but the amount of increase is very small and may be an anomaly. EFFECT OF SALINITY SHOCK ON THE 58 KD AND 48 KD PROTEINS RECOGNIZED BY ANTI-HSP 60: Figure 8 shows the western blot analysis of the heat shock proteins present in different conditions of salinity shock. P. squamatus are thought to naturally reside in sea water at a salinity of 33.2 parts per thousand (ppt). Salinities of 10 ppt above and below this value were tested to see if a heat shock response was induced. In the figure, the first and third lanes contain the proteins from the shocked animals. Lanes two and four contain the instant ocean and the normal control respectively. The fifth lane contains the HSP 60 molecular weight standard. Analysis of the darkness of each protein band reveals that the levels of protein that cross-react with the anti- HSP 60 antibody increase in both of the shock conditions relative to the controls. This trend is observed in both the higher molecular weight (58 KD) and the lower molecular weight (48 kD) proteins, although much more dramatically in the 58 kD protein. Figure 9 shows this trend more clearly in a quantitative analysis of the relative intensities of each protein band based on the JAVA image processing data. The intensity reading directly correlates to the amount of protein present. Another point of interest is that there does not appear to be a significant difference in the amount of protein present between the instant ocean control and the normal sea water control. Therefore, it may be reasonable to assume that the instant ocean does not have any profound effects on heat shock protein activity in the organism. Figures 10 and 11 show the JAVA image processing analysis of the two other salinity shock experiments performed. Again, the specific relative intensity values of each protein band can be found in Table 1 under the "HSP 60 (58 kD)“ and the "HSP 60 (48 kD)" columns. Figure 10 reports a decrease in the amount of the 58 kD protein in the shock condition relative to the control (33.2 ppt) and a steady amount in the 48 kD protein. Figure 11 shows the control organism (33.2 ppt) to have a dramatically higher amount of both the 58 kD and the 48 kD proteins. However, this result may not be significant because the water that was removed after the experiment appeared to be contaminated with some sort of milky substance. This contamination may have accounted for the increased levels of heat shock proteins in that particular animal. If the 33.2 ppt control is disregarded, and the shock conditions are compared to the normal sea water control, it appears as if the salinity change induces a small increase in the levels of the heat shock proteins. However, the change is not dramatic enough to be able to draw any conclusions. This and the contradictory data seen in Figure 10 make it difficult to predict any conclusive trends. DISCUSSION The initial screening to determine which heat shock proteins are present in Psolus squamatus revealed that there are five proteins that cross¬ react with the anti-HSP 60 antibody. These five proteins are 116 kD, 58 KD, 55 KD, 48 kD, and 40 kD in size and span a molecular weight range of 76 kD. A heat shock protein family is generally characterized by sequence homology among its members and specific binding of its members to the same antibody. The anti-HSP 60 antibody used to probe the blots was polyclonal. This may have decreased the specificity of the cross-reaction between the antibody and the proteins on the blots. Of particular interest is the 116 kD protein found in P. squamatus that cross-reacts to the anti-HSP 60 antibody. This protein occurs greatly out of the size range of the other anti-HSP 60 binding proteins and has not been documented before. This binding may be a result of the polyclonal nature of the primary antibody used and may not necessarily mean that the protein belongs to the HSP 60 protein family. Nevertheless, the fact that there are a total of five proteins that cross-react with the anti-HSP 60 antibody may give some indication as to why Psolus squamatus has been so successful at surviving in such a wide variety of environments. The sum of these proteins may better prepare the organism to survive environmental changes and stresses, accounting for its abundance and success in the Monterey Canyon. In addition to the constitutive HSP 60 proteins that aid the organism in its survival, this study has also documented a marked increase in the levels of these same proteins under stress conditions. The heat shock experiments showed that HSP 60 protein production is amplified under a temperature shock of about 13°C. However, at super-shock conditions of about 20°C, the amount of protein present in the animal drops significantly. It appears as if the organism can respond to the heat shock with the HSP induction response to a certain threshold temperature. Beyond this point, the organism may be impaired in its ability to synthesize new proteins. Furthermore, the constitutive heat shock proteins may also be breaking down at these super- ambient temperatures. Again, protein degradation was seen at temperatures of about 20°C and P. squamatus have been seen to survive in temperatures of up to 22°C. There appears to be a direct correlation between the decrease in heat shock protein activity and the deaths of the animals, as they occur within the same general temperature range. The results of the salinity shock experiments were not as clear cut. Much more work can be done to continue this project. The salinity and heat shock experiments can be rerun in gradients with smaller salinity and temperature increments in order to better predict the trends occurring. Time course experiments could be run in order to determine at which specific points of the shock protein activity is occurring. The five different proteins that cross-reacted with the anti-HSP 60 antibody could be isolated, sequenced and studied in order to determine whether or not each of these proteins are really HSP 60 proteins. This would be especially interesting to do to the 116 kD protein because it seems to be a previously unidentified heat shock protein. The proteins could also be separated on two-dimensional gels on the basis of both size and charge in order to get better resolution of the proteins. The induction of HSP 60 proteins could be studied at the level of gene expression by isolating and quantifying RNA during different stages of the shock. All of these experiments would be useful in better characterizing the heat shock response in this organism. Learning more about the heat shock proteins and the biochemical activity occurring in Psolus squamatus may give important insights into its heartiness, its successful survival in many different environments, and the reasons for its dominant presence in the benthic seas. ACKNOWLEDGMENTS First and foremost, I would like to thank the Levine lab. It got a little crazy at times, but it was always fun. Thank you to my advisor, Dr. Paul Levine, for his advice, support, and encouragement throughout my project. Thank you to Julie Golden for her patience and kindness and to Jan Van Kampen for letting us invade his lab space. Thanks to my lab mates Theresa, Dan, and Greg for helping me out in lab, for our Big Mac lunches, our pizza and Chinese food dinners, and for making this quarter a blast. Thank you to Chuck Baxter for all of his wise advice and for sharing his enthusiasm. Thanks to all of Hopkins Marine Station and the spring quarter class. It was great getting to know everyone. I had a great time and learned a lot. Thanks for making this the greatest quarter ever!! LITERATURE CITED 1. Burnette, W.N. 1981. "Western blotting": electrophoretic transfer of proteins from sodium dodecyl sulfate-polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal. Biochem. 112 : 195-203 2. Carlsten, Christopher. 1991. Respiration in Psolus squamatus. Unpublished manuscript available at Hopkins Marine Station in Pacific Grove, CA. 3. Harlow, Ed and David Lane (eds.). 1988. Antibodies, a Laboratory Manual. Cold Spring Harbor Laboratory. Cold Spring Harbor Laboratory Press. Cold Spring Harbor, New York. 4. Kaufmann, S.H.E. (ed.). 1991. Heat Shock Proteins and Immune Response. Springer-Verlag. Berlin Heidelberg. 5. Laemmli, U. K. 1970. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature (London) 227 : 680-685. 6. Lindquist, Susan. 1986. The Heat-Shock Response. Ann. Rev. Biochem. 55: 1151-1185. 7. Lowry, O. H., N.J. Rosenbrough, A.L. Farr, and R.J. Randall. 1951. Protein determination with the Folin phenol reagents. J. Biol. Chem. 193: 265-275. 8. Morimoto, Richard, Alfred Tissieres, and Costa Georgopoulos (eds). 1990. Stress Proteins in Biology and Medicine. Cold Spring Harbor Laboratory Press. Cold Spring Harbor, New York. 8 ataaaa. 54 9- 8292222 2222 EE- ooob ataaee poooo ---- ooooo - — — d kaaaaae 00 oO0 88 22 . 805 ao 5 II 8. 88 8aa 0 II 5 5 5 EEE ooOO ooo NOO o —— 55 88 290 II 5 8 — . o o o o 50 . Pod oO 8 8 ooo oooO ON oo NOO - a a o 889 888 ao O O C. III — 5 — - 0 II o 1 2 - — oo - 2 88 —— 2 o t 0 fIII 9 5 Oo + 10 50 229 0 888888 a IIIIII No 2 —v oooo 28 aa 0 88 8 5 0 85 o 50 2 - 1 8 5 EEE OON o ooo- OO a- oo OO FIGURE LEGEND FIGURE 1: Western Blot: HSP 60 Proteins Present in Initial Screening of P. squamatus: The two lanes contain protein from an unshocked P. squamatus. The left lane contains twice as much protein as the right lane. The blot was probed with anti-HSP 60 antibody. FIGURE 2: Western Blot: Five Proteins Cross-React with Anti-HSP 60: The three lanes contain protein from an unshocked specimen (same as in Figure 1), protein from a control organism in a heat shock experiment, and protein from a control organism in a salinity shock experiment respectively. The blots were probed with anti-HSP 60 antibody. The five different proteins that cross-react with the antibody are marked. FIGURE 3: Western Blot: HSP 60 Proteins Due to Heat Shock Conditions: The first three lanes contain protein from organisms shocked for two hours at 5°C (control), 12°C, and 19°C. The last lane contains the HSP 60 standard. The blot was probed with anti-HSP 60 antibody. FIGURE 4: Relative Intensities of HSP 60 Protein Bands Under Different Heat Shock Conditions (5/25/93) FIGURE 5: Relative Intensities of HSP 60 Protein Bands Under Different Heat Shock Conditions (5/20/93) FIGURE 6: Relative Intensities of HSP 60 Protein Bands Under Different Heat Shock Conditions (5/18/93) FIGURE 7: Relative Intensities of HSP 60 Protein Bands Under Different Heat Shock Conditions (5/13/93) FIGURE 8: Western Blot: HSP 60 Proteins Due to Salinity Shock Conditions: The first four lanes contain protein from organisms shocked at 23.2 g/L, 33.2 g/L (instant ocean control), 43.2 g/L, and in normal sea water (normal control). The HSP 60 standard is in the fifth lane. The blot was probed with anti-HSP 60 antibody. FIGURE 9: Relative Intensities of HSP 60 Protein Bands Under Different Salinity Shock Conditions (5/11/93) FIGURE 10: Relative Intensities of HSP 60 Protein Bands Under Different Salinity Shock Conditions (5/13/93) FIGURE 11: Relative Intensities of HSP 60 Protein Bands Under Different Salinity Shock Conditions (5/18/93) HSP 60 Proteins present in Psolus 116- 84- 58 48.5- — 36.5 Figure 1 Five Proteins Cross-react with Anti-HSP 60 - 180- -116- -84- -58- -48.5- -36.5 -26.6- Figure 2 HSP 60 Proteins due to Heat Shock 84- 58 48.5 36.5 Figure 3 0 + Heat Shock 5/25/93 HSP 48 HSP 58 Heat Shock Proteins Figure 4 E5C E 12 C E 190 Heat Shock 5/20/93 HSP 60 (58 kD) HSP 60 (48 kD) Heat Shock Proteins Figure 5 5.0 C E 13.0 C Heat Shock 5/18/93 HSP 60 (58 kD) HSP 60 (48 kD) Heat Shock Proteins Figure 6 5.0 C E 19.6 C 2 0 + Heat Shock 5/13/93 HSP 60 (58 kD) HSP 60 (48 kD) Heat Shock Proteins Figure 7 E5C E 20.4 C HSP 60 Proteins due to Salinity Shock aa e 0 Z 84- —— — 58- — — 48.5- 36.5- Figure 8 Salinity Shock 5/11/93 HSP 60 (58 kD) HSP 60 (48 kD) Heat Shock Proteins Figure 9 23.2 ppt 33.2 ppt 43.2 ppt E Normal SW* 15- 0 + Salinity Shock 5/13/93 HSP 60 (58 kD) HSP 60 (48 kD) Heat Shock Proteins Figure 10 23.2 ppt E 33.2 ppt 0 + Salinity Shock 5/18/93 HSP 60 (58 kD) HSP 60 (48 kD) Heat Shock Proteins Figure 11 23.2 ppt E 33.2 ppt 43.2 ppt Normal SW*